Catalyzed Diels-Alder Reaction Research Articles

Unravelling the Mechanism and Governing Factors in Lewis Acid and Non-Covalent Diels-Alder Catalysis: Different Perspectives.

In the current literature, many non-covalent interaction (NCI) donors have been proposed that can potentially catalyze Diels-Alder (DA) reactions. In this study, a detailed analysis of the governing factors in Lewis acid and non-covalent catalysis of three types of DA reactions was carried out, for which we selected a set of hydrogen-, halogen-, chalcogen-, and pnictogen-bond donors. We found that the more stable the NCI donor-dienophile complex, the larger the reduction in DA activation energy. We also showed that for active catalysts, a significant part of the stabilization was caused by orbital interactions, though electrostatic interactions dominated. Traditionally, DA catalysis was attributed to improved orbital interactions between the diene and dienophile. Recently, Vermeeren and co-workers applied the activation strain model (ASM) of reactivity, combined with the Ziegler-Rauk-type energy decomposition analysis (EDA), to catalyzed DA reactions in which energy contributions for the uncatalyzed and catalyzed reaction were compared at a consistent geometry. They concluded that reduced Pauli repulsion energy, and not enhanced orbital interaction energy, was responsible for the catalysis. However, when the degree of asynchronicity of the reaction is altered to a large extent, as is the case for our studied hetero-DA reactions, the ASM should be employed with caution. We therefore proposed an alternative and complementary approach, in which EDA values for the catalyzed transition-state geometry, with the catalyst present or deleted, can be compared one to one, directly measuring the effect of the catalyst on the physical factors governing the DA catalysis. We discovered that enhanced orbital interactions are often the main driver for catalysis and that Pauli repulsion plays a varying role.

BF3–Catalyzed Diels–Alder Reaction between Butadiene and Methyl Acrylate in Aqueous Solution—An URVA and Local Vibrational Mode Study

In this study we investigate the Diels–Alder reaction between methyl acrylate and butadiene, which is catalyzed by BF3 Lewis acid in explicit water solution, using URVA and Local Mode Analysis as major tools complemented with NBO, electron density and ring puckering analyses. We considered four different starting orientations of methyl acrylate and butadiene, which led to 16 DA reactions in total. In order to isolate the catalytic effects of the BF3 catalyst and those of the water environment and exploring how these effects are synchronized, we systematically compared the non-catalyzed reaction in gas phase and aqueous solution with the catalyzed reaction in gas phase and aqueous solution. Gas phase studies were performed at the B3LYP/6-311+G(2d,p) level of theory and studies in aqueous solution were performed utilizing a QM/MM approach at the B3LYP/6-311+G(2d,p)/AMBER level of theory. The URVA results revealed reaction path curvature profiles with an overall similar pattern for all 16 reactions showing the same sequence of CC single bond formation for all of them. In contrast to the parent DA reaction with symmetric substrates causing a synchronous bond formation process, here, first the new CC single bond on the CH2 side of methyl acrylate is formed followed by the CC bond at the ester side. As for the parent DA reaction, both bond formation events occur after the TS, i.e., they do not contribute to the energy barrier. What determines the barrier is the preparation process for CC bond formation, including the approach diene and dienophile, CC bond length changes and, in particular, rehybridization of the carbon atoms involved in the formation of the cyclohexene ring. This process is modified by both the BF3 catalyst and the water environment, where both work in a hand-in-hand fashion leading to the lowest energy barrier of 9.06 kcal/mol found for the catalyzed reaction R1 in aqueous solution compared to the highest energy barrier of 20.68 kcal/mol found for the non-catalyzed reaction R1 in the gas phase. The major effect of the BF3 catalyst is the increased mutual polarization and the increased charge transfer between methyl acrylate and butadiene, facilitating the approach of diene and dienophile and the pyramidalization of the CC atoms involved in the ring formation, which leads to a lowering of the activation energy. The catalytic effect of water solution is threefold. The polar environment leads also to increased polarization and charge transfer between the reacting species, similar as in the case of the BF3 catalyst, although to a smaller extend. More important is the formation of hydrogen bonds with the reaction complex, which are stronger for the TS than for the reactant, thus stabilizing the TS which leads to a further reduction of the activation energy. As shown by the ring puckering analysis, the third effect of water is space confinement of the reacting partners, conserving the boat form of the six-member ring from the entrance to the exit reaction channel. In summary, URVA combined with LMA has led to a clearer picture on how both BF3 catalyst and aqueous environment in a synchronized effort lower the reaction barrier. These new insights will serve to further fine-tune the DA reaction of methyl acrylate and butadiene and DA reactions in general.

Mechanism of the Stereoselective Catalysis of Diels-Alderase PyrE3 Involved in Pyrroindomycin Biosynthesis.

The biosynthesis of pyrroindomycins A and B features a complexity-building [4 + 2] cycloaddition cascade, which generates the spirotetramate core under the catalytic effects of monofunctional Diels-Alderases PyrE3 and PyrI4. We recently showed that the main functions of PyrI4 include acid catalysis and induced-fit/conformational selection. We now present quantum mechanical and molecular dynamics studies implicating a different mode of action by PyrE3, which prearranges an anionic polyene substrate into a high-energy reactive conformation at which an inverse-electron-demand Diels-Alder reaction can occur with a low barrier. Stereoselection is realized by strong binding interactions at the endo stereochemical relationship and a local steric constraint on the endo-1,3-diene unit. These findings, illustrating distinct mechanisms for PyrE3 and PyrI4, highlight how nature has evolved multiple ways to catalyze Diels-Alder reactions.

Total Synthesis of (+)-Kingianin A by Enantioselective Cycloaddition of Strained Cyclobutenone

AbstractWe report here the first asymmetric total synthesis of (+)-kingianin A via dimerization of an enantioenriched bicyclo[4.2.0]octadiene. The synthesis features a chiral oxazaborolidinium ion catalyzed Diels–Alder reaction of strained cyclobutenone and stereoselective functionalization of the cyclobutane ring. A preliminary biological study indicated that (+)-kingianin A exhibits potent anticancer activities.

A Direct Organocatalytic Enantioselective Route to Functionalized trans-Diels-Alder Products Having the Norcarane Scaffold.

An enantioselective methodology to construct trans-Diels-Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo-halogen effect to direct an endo-selective, secondary-amine catalyzed Diels-Alder reaction allowing for the subsequent formation of trans-Diels-Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α-brominated or α-pseudo-halogenated enone to form a fleeting cis-Diels-Alder intermediate. The endo-transition state-enhanced by the (pseudo-)halogen effect-sets the stereochemistry that allows for a subsequent SN 2-like reaction at a tertiary center to obtain the trans-Diels-Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

A Direct Organocatalytic Enantioselective Route to Functionalizedtrans‐Diels–Alder Products Having the Norcarane Scaffold

AbstractAn enantioselective methodology to construct trans‐Diels–Alder scaffolds by organocatalysis with excellent selectivity, high yield and up to five contiguous stereocenters is presented. The reaction concept integrates the halogen effect and a novel discovered pseudo‐halogen effect to direct an endo‐selective, secondary‐amine catalyzed Diels–Alder reaction allowing for the subsequent formation of trans‐Diels–Alder cycloadducts featuring the norcarene scaffold. The methodology relies on the reaction between an in situ generated trienamine and an α‐brominated or α‐pseudo‐halogenated enone to form a fleeting cis‐Diels–Alder intermediate. The endo‐transition state‐enhanced by the (pseudo‐)halogen effect‐sets the stereochemistry that allows for a subsequent SN2‐like reaction at a tertiary center to obtain the trans‐Diels–Alder scaffold. The mechanism was investigated and supported by experimental results as well as computational studies.

Water Modulated Diastereoselective Synthesis of cis/trans-Spiro[indoline-3,6'-naphtho[2,3-c]carbazoles

p-TsOH catalyzed Diels-Alder reaction of 2-(1-alkylindol-3-yl)naphthalene-1,4-diones and 3-phenacylideneoxindoles showed fascinating diastereoselectivity. The reaction with the hydrated p-TsOH afforded trans-isomers of dihydrospiro[indoline-3,6'-naphtho[2,3-c]carbazoles] as major products. Alternatively, the reaction with anhydrous p-TsOH under a Dean and Stark apparatus predominately gave cis-isomer of dihydrospiro[indoline-3,6'-naphtho[2,3-c]carbazoles]. On the other hand, the similar p-TsOH catalyzed reaction of 2-(indol-3-yl)naphthalene-1,4-diones with 3-arylideneindolin-2-ones afforded cis/trans-isomers of dihydrospiro[indoline-3,6'-naphtho[2,3-c]carbazoles]. Additionally, the p-TsOH catalyzed reaction of 2-(indol-3-yl)naphthalene-1,4-diones with 2-arylidene-1,3-indanediones gave the expected spiro[indene-2,6'-naphtho[2,3-c]carbazoles] in satisfactory yields.

Theoretical Insight into the Reversal of Chemoselectivity in Diels-Alder Reactions of α,β-Unsaturated Aldehydes and Ketones Catalyzed by Brønsted and Lewis Acids

Experimentally, a reversal of chemoselectivity has been observed in catalyzed Diels–Alder reactions of α,β-unsaturated aldehydes (e.g., (2E)-but-2-enal) and ketones (e.g., 2-hexen-4-one) with cyclopentadiene. Indeed, using the triflimidic Brønsted acid Tf2NH as catalyst, the reaction gave a Diels–Alder adduct derived from α,β-unsaturated ketone as a major product. On the other hand, the use of tris(pentafluorophenyl)borane B(C6F5)3 bulky Lewis acid as catalyst gave mainly the cycloadduct of α,β-unsaturated aldehyde as a major product. Our aim in the present work is to put in evidence the role of the catalyst in the reversal of the chemoselectivity of the catalyzed Diels–Alder reactions of (2E)-but-2-enal and 2-Hexen-4-one with cyclopentadiene. The calculations were performed at the ωB97XD/6-311G(d,p) level of theory and the solvent effects of dichloromethane were taken into account using the PCM solvation model. The obtained results are in good agreement with experimental outcomes.

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

Convenient construction of spiro[indoline-3,5'-pyrrolo[3,4-c]carbazole] and spiro[indene-2,5'-pyrrolo[3,4-c]carbazole] via acid-catalyzed Diels-Alder reaction

p-TsOH catalyzed Diels-Alder reaction of 3-(indol-3-yl)maleimides with 3-phenacylideneoxindoles in toluene at 80 °C for two hours afforded cis/trans isomers of 3a',4′,6′,10c'-tetrahydrospiro[indoline-3,5′-pyrrolo[3,4-c]carbazoles] in nearly comparable yields, which could be easily converted to the corresponding 4′,6′-dihydrospiro[indoline-3,5′-pyrrolo[3,4-c]carbazole] in high yields and with high diastereoselectivity by further DDQ oxidation. Additionally, the similar reaction of 3-(indol-3-yl)maleimides with 2-arylidene-1,3-indanediones in toluene 80 °C and sequential DDQ oxidation afforded functionalized dihydrospiro[indene-2,5′-pyrrolo[3,4-c]carbazoles] as major products.

Lithium Cation-Catalyzed Benzene Diels-Alder Reaction: Insights on the Molecular Mechanism Within the Molecular Electron Density Theory.

The lithium cation Li+-catalyzed Diels-Alder (DA) reactions of benzene toward a series of acetylenes of improved nucleophilicity can be described within the context of the molecular electron density theory (MEDT) at the ωB97XD/6-311G(d,p) level. Conceptual density functional theory indices characterize the crown ether solvated complex benzene-lithium Bz-Li-Cro as a superelectrophile. Coordination of a lithium cation to benzene does not change substantially the electron localization function electronic structure of benzene. The DA reaction of Bz-Li-Cro with acetylene shows a reduction of the energy of activation of 6.9 kcal·mol-1, which is not sufficient for the reaction to take place, thus demanding the participation of strong nucleophilic acetylenes. DA reactions of complexes Bz-M-Cro (M = Li, Na, and K) are decelerated with the decrease of the ionization potential of the alkali metal. The one-step mechanism of these lithium cation Li+-catalyzed DA reactions changes to a two-step one for the reaction with dimethyl propynamine. The present MEDT study proves that analysis of the electrophilicity and nucleophilicity indices is an excellent tool for experimental organic chemists to understand, even to predict, the chemical organic reactivity.

How Lewis Acids Catalyze Diels–Alder Reactions

AbstractThe Lewis acid(LA)‐catalyzed Diels–Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled‐cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I2<SnCl4<TiCl4<ZnCl2<BF3<AlCl3. Emerging from our activation strain and Kohn–Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels–Alder reaction by a diminished Pauli repulsion between the π‐electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels–Alder reaction by enhancing the donor–acceptor [HOMOdiene–LUMOdienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.

How Lewis Acids Catalyze Diels-Alder Reactions.

The Lewis acid(LA)‐catalyzed Diels–Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled‐cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I2<SnCl4<TiCl4<ZnCl2<BF3<AlCl3. Emerging from our activation strain and Kohn–Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels–Alder reaction by a diminished Pauli repulsion between the π‐electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels–Alder reaction by enhancing the donor–acceptor [HOMOdiene–LUMOdienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.

Origin of rate enhancement and asynchronicity in iminium catalyzed Diels-Alder reactions.

The Diels–Alder reactions between cyclopentadiene and various α,β-unsaturated aldehyde, imine, and iminium dienophiles were quantum chemically studied using a combined density functional theory and coupled-cluster theory approach. Simple iminium catalysts accelerate the Diels–Alder reactions by lowering the reaction barrier up to 20 kcal mol−1 compared to the parent aldehyde and imine reactions. Our detailed activation strain and Kohn–Sham molecular orbital analyses reveal that the iminium catalysts enhance the reactivity by reducing the steric (Pauli) repulsion between the diene and dienophile, which originates from both a more asynchronous reaction mode and a more significant polarization of the π-system away from the incoming diene compared to aldehyde and imine analogs. Notably, we establish that the driving force behind the asynchronicity of the herein studied Diels–Alder reactions is the relief of destabilizing steric (Pauli) repulsion and not the orbital interaction between the terminal carbon of the dienophile and the diene, which is the widely accepted rationale.

Asymmetric catalysis mediated by a mirror symmetry-broken helical nanoribbon

Although chirality has been recognized as an essential entity for life, it still remains a big mystery how the homochirality in nature emerged in essential biomolecules. Certain achiral motifs are known to assemble into chiral nanostructures. In rare cases, their absolute geometries are enantiomerically biased by mirror symmetry breaking. Here we report the first example of asymmetric catalysis by using a mirror symmetry-broken helical nanoribbon as the ligand. We obtain this helical nanoribbon from a benzoic acid appended achiral benzene-1,3,5-tricarboxamide by its helical supramolecular assembly and employ it for the Cu2+-catalyzed Diels–Alder reaction. By thorough optimization of the reaction (conversion: > 99%, turnover number: ~90), the enantiomeric excess eventually reaches 46% (major/minor enantiomers = 73/27). We also confirm that the helical nanoribbon indeed carries helically twisted binding sites for Cu2+. Our achievement may provide the fundamental breakthrough for producing optically active molecules from a mixture of totally achiral motifs.

Glycyrrhizic acid based self-assembled helical nanostructures as scaffolds for asymmetric Diels-Alder reaction

Glycyrrhizic acid (GA), as a traditional herbal, can self-assemble into helical nanofiber in the water. The formed helical nanostructures can be employed as scaffolds for asymmetric Diels-Alder reaction. Through co-assembling with a series of achiral copper-ligands, the chirality of GA helical nanostructures can be transferred to catalytic site, and resulted assemblies showed moderated enantioselectivity toward catalysis of Diels-Alder reaction.

Catalytic Diels–Alder Reaction of α,β-Unsaturated Methyl Esters

Catalytic Diels–Alder Reaction of α,β-Unsaturated Methyl Esters

Scalable and Highly Diastereo- and Enantioselective Catalytic Diels-Alder Reaction of α,β-Unsaturated Methyl Esters.

Despite tremendous advances in enantioselective catalysis of the Diels-Alder reaction, the use of simple α,β-unsaturated esters, one of the most abundant and useful class of dienophiles, is still severely limited in scope due to their low reactivity. We report here a catalytic asymmetric Diels-Alder methodology for a large variety of α,β-unsaturated methyl esters and different dienes based on extremely reactive silylium imidodiphosphorimidate (IDPi) Lewis acids. Mechanistic insights from accurate domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) calculations rationalize the catalyst control and stereochemical outcome.

Electrophilic Phosphonium Cations as Lewis Acid Catalysts in Diels–Alder Reactions and Nazarov Cyclizations

The highly electrophilic fluorophosphonium cation [(C6F5)3PF]+[B(C6F5)4]− is shown to catalyze Diels–Alder reactions of challenging dienophile/enophile combinations and Nazarov cyclizations of various precursors. Several other electrophilic phosphonium cations (EPCs) have been tested for comparison. This systematic study demonstrates the power of these Lewis acids to act as catalysts for synthetically useful pericyclic reactions.