Bifunctional Hydrogen Bond Donor-Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement

The selectivity and rate enhancement of bifunctional hydrogen bond donor-catalyzed Diels–Alder reactions between cyclopentadiene and acrolein were quantum chemically studied using density functional theory in combination with coupled-cluster theory. (Thio)ureas render the studied Diels–Alder cycloaddition reactions exo selective and induce a significant acceleration of this process by lowering the reaction barrier by up to 7 kcal mol⁻¹. Our activation strain and Kohn–Sham molecular orbital analyses uncover that these organocatalysts enhance the Diels–Alder reactivity by reducing the Pauli repulsion between the closed-shell filled π-orbitals of the diene and dienophile, by polarizing the π-orbitals away from the reactive center and not by making the orbital interactions between the reactants stronger. In addition, we establish that the unprecedented exo selectivity of the hydrogen bond donor-catalyzed Diels–Alder reactions is directly related to the larger degree of asynchronicity along this reaction pathway, which is manifested in a relief of destabilizing activation strain and Pauli repulsion.     

Two-Way Catalysis in a Diels–Alder Reaction Limits Inhibition Induced by an External Electric Field

Oriented external electric fields (EEFs) act as catalysts that can induce selectivity in chemical reactions. The responses of the Diels–Alder (DA) reaction between butadiene and ethylene (BDE-DA) as well as cyclopentadiene and ethylene (CPDE-DA) towards EEF stimuli are investigated here using density functional theory (B3LYP) calculations. EEF is a vector that catalyzes the reaction in one direction while inhibiting it in the opposite direction. Here we report that the inhibitive direction becomes rate-enhancing after some increase in the EEF. The EEF value that brings about the maximum possible inhibition for the reaction is defined as the electrostatic resistance point (ERP). The possibility of both normal and inverse electron-demand DA reactions causes catalytic activity in both directions of the EEF starting at a unique ERP value. The C5 substituents of cyclopentadiene control the ERP values depending upon the resistance power that the functional group provides against the EEF. The endo and exo diastereomeric transition states of the DA reaction have distinct ERP values and the difference (ΔERP) provides the through-space electrostatic contribution to the stereoselectivity on a relative scale. Thus, the ERP values can be used as a gauge for the electrostatic interactions between substituent groups and external stimuli.     

Oriented Electric Fields Accelerate Diels–Alder Reactions and Control the endo/exo Selectivity

Herein we demonstrate that an external electric field (EEF) acts as an accessory catalyst/inhibitor for Diels–Alder (DA) reactions. When the EEF is oriented along the “reaction axis” (the coordinate of approach of the reactants in the reaction path), the barrier of the DA reactions is lowered by a significant amount, equivalent to rate enhancements by 4–6 orders of magnitude. Simply flipping the EEF direction has the opposite effect, and the EEF acts as an inhibitor. Additionally, an EEF oriented perpendicular to the “reaction axis” in the direction of the individual molecule dipoles can change the endo/exo selectivity, favouring one or the other depending on the positive/negative directions of the EEF vis‐à‐vis the individual molecular dipole. At some critical value of the EEF along the “reaction axis”, there is a crossover to a stepwise mechanism that involves a zwitterionic intermediate. The valence bond diagram model is used to comprehend these trends and to derive a selection rule for EEF effects on chemical reactions: an EEF aligned in the direction of the electron flow between the reactants will lower the reaction barrier. It is shown that the exo/endo control by the EEF is not associated with changes in secondary orbital interactions.     

Cationic Chiral Pd‐Catalyzed “Acetylenic” Diels–Alder Reaction: Computational Analysis of Reversal in Enantioselectivity

The highly enantioselective Diels–Alder reaction of acetylenic dienophiles is shown to be effectively catalyzed by cationic chiral palladium complexes. Not only the degree but also the sense of enantioselectivity critically depends on the steric demand of ligands. Computational analyses indicate that the steric demand does not affect the endo/exo‐selectivity but the enantioface selectivity of dienes.     

Evolution of a Multicomponent System: Computational and Mechanistic Studies on the Chemo‐ and Stereoselectivity of a Divergent Process

The evolution of a ternary molecular system (imine, diene and nitrile) is analyzed to disclose the pathways leading to a divergent synthetic outcome. The Lewis acid catalyzed reaction between cyclohexadiene, 2‐phenyl‐indol‐3‐one and acetonitrile yields the imino‐Diels–Alder adduct as the major product together with minor amounts of the Mannich–Ritter‐amidine product. The experimental and computational data show that the relative orientation of the initial reactants dictates the synthetic outcome. The exo approach between imine and diene leads to the Diels–Alder adduct in a concerted process, whereas the endo mode leads to a polarized intermediate, which is trapped by acetonitrile to yield the multicomponent adduct.     

Stacking and Electrostatic Interactions Drive the Stereoselectivity of Silylium‐Ion Asymmetric Counteranion‐Directed Catalysis

Computational analysis shows that the enantioselectivity of asymmetric Lewis‐acid organocatalysis of the Diels–Alder cycloaddition of cyclopentadiene to cinnamates arises from stacking interactions that favor the addition of the diene to the more hindered face of the dienophile, while electrostatic interactions control the diastereoselectivity by selectively stabilizing the endo transition state. These results not only explain the stereoselectivity of these silylium‐ion‐ACDC reactions but should also guide the development of more effective ion‐pairing asymmetric organocatalysts.     

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 [HOMO_diene–LUMO_dienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.     

Origin of Orthogonality of Strain‐Promoted Click Reactions

Site‐specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a set of strain‐promoted click‐type cycloaddition reactions of n‐propyl azide, 3‐benzyl tetrazine and 3‐benzyl‐6‐methyl tetrazine with cyclooctenes/ynes, in which we aim to address all relevant structural details of the reactants. Our calculations have included the obligatory handles used to attach the label and biomolecule as these can critically influence the stereochemistry and electron demand of the reaction. We systematically computed orbital gaps, activation and distortion energies using density functional theory and determined experimental rates for validation. Our results challenge the current paradigm of the inverse electron demand for this class of reactions. We found that the ubiquitous handles, when next to the triple bond of cyclooctynes, can switch the Diels–Alder type ligations to normal electron demand, a class we term as SPINEDAC reactions. Electron donating substituents on tetrazine can enhance normal demand but also increase distortion penalties. The presence and isomeric configuration of handles thus determine the reaction speed and regioselectivity. Our findings can be directly utilized in engineering genuine cycloaddition click chemistries for biological labeling.     

Selective Modification of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs) through Diels–Alder Cycloadditions on Dehydroalanine Residues

We report the late-stage chemical modification of ribosomally synthesized and post-translationally modified peptides (RIPPs) by Diels–Alder cycloadditions to naturally occurring dehydroalanines. The tail region of the thiopeptide thiostrepton could be modified selectively and efficiently under microwave heating and transition-metal-free conditions. The Diels–Alder adducts were isolated and the different site- and endo/exo isomers were identified by 1D/2D ¹H NMR. Via efficient modification of the thiopeptide nosiheptide and the lanthipeptide nisin Z the generality of the method was established. Minimum inhibitory concentration (MIC) assays of the purified thiostrepton Diels–Alder products against thiostrepton-susceptible strains displayed high activities comparable to that of native thiostrepton. These Diels–Alder products were also subjected successfully to inverse-electron-demand Diels–Alder reactions with a variety of functionalized tetrazines, demonstrating the utility of this method for labeling of RiPPs.     

Liquid‐Crystalline Ionic Liquids as Ordered Reaction Media for the Diels–Alder Reaction

Liquid‐crystalline ionic liquids (LCILs) are ordered materials that have untapped potential to be used as reaction media for synthetic chemistry. This paper investigates the potential for the ordered structures of LCILs to influence the stereochemical outcome of the Diels–Alder reaction between cyclopentadiene and methyl acrylate. The ratio of endo‐ to exo‐product from this reaction was monitored for a range of ionic liquids (ILs) and LCILs. Comparison of the endo:exo ratios in these reactions as a function of cation, anion and liquid crystallinity of the reaction media, allowed for the effects of liquid crystallinity to be distinguished from anion effects or cation alkyl chain length effects. These data strongly suggest that the proportion of exo‐product increases as the reaction media is changed from an isotropic IL to a LCIL. A detailed molecular dynamics (MD) study suggests that this effect is related to different hydrogen bonding interactions between the reaction media and the exo‐ and endo‐transition states in solvents with layered, smectic ordering compared to those that are isotropic.     

Heterogeneous asymmetric Diels–Alder reactions using a copper–chiral bis(oxazoline) complex immobilized on mesoporous silica

A chiral bis(oxazoline)–copper complex was immobilized onto mesoporous silica and the resulting heterogeneous catalyst was employed in asymmetric Diels–Alder reactions. Reactions using the catalyst exhibited good enantioselectivity of 78% enantiomeric excess and endo/exo-selectivity (17:1) better than the corresponding homogeneous reaction. The catalyst could be easily recovered and reused several times without significant loss of the remarkable reactivity, diastereoselectivity and enantioselectivity.     

Theoretical and Structural Analysis of Long CC Bonds in the Adducts of Polycyanoethylene and Anthracene Derivatives and Their Connection to the Reversibility of Diels–Alder Reactions

X‐ray structure determinations on four Diels–Alder adducts derived from the reactions of cyano‐ and ester‐substituted alkenes with anthracene and 9,10‐dimethylanthracene have shown the bonds formed in the adduction to be particularly long. Their lengths range from 1.58 to 1.62 Å, some of the longest known for Diels–Alder adducts. Formation of the four adducts is detectably reversible at ambient temperature and is associated with free energies of reaction ranging from ?2.5 to ?40.6 kJ mol^?1. The solution equilibria have been experimentally characterised by NMR spectroscopy. Density‐functional‐theory calculations at the MPW1K/6‐31+G(d,p) level with PCM solvation agree with experiment with average errors of 6 kJ mol^?1 in free energies of reaction and structural agreement in adduct bond lengths of 0.013 Å. To understand more fully the cause of the reversibility and its relationship to the long adduct bond lengths, natural‐bond‐orbital (NBO) analysis was applied to quantify donor–acceptor interactions within the molecules. Both electron donation into the σ*‐anti‐bonding orbital of the adduct bond and electron withdrawal from the σ‐bonding orbital are found to be responsible for this bond elongation.     

Stereoselective synthesis of chiral hydrocarbazoles via the catalytic Diels–Alder reaction of siloxyvinylindole and cyclic Z-olefin

The catalytic Diels–Alder reaction of siloxyvinylindole and cyclic Z-olefin derived from pyroglutamic acid gave optically active substituted hydrocarbazoles. The exo/endo selectivity of this reaction could be controlled by using an appropriate Lewis acid. Scandium triflate gave high exo-selectivity and copper triflate gave moderate endo-selectivity. Subsequent stereoselective alkylation of the cycloadduct led to the synthesis of highly substituted hydrocarbazoles with five continuous chiral centers including a quaternary carbon.     

Enantioselective catalysis using planar chiral η6-arene chromium complexes: 1,2-diols as cycloaddition catalysts

A highly selective Diels–Alder catalyst has been prepared from a commercially available tetrahydronaphthalene diol. Stereocontrol is greatly enhanced by introduction of a planar chiral arene chromium tricarbonyl group, achieved by face selective complexation. The factors influencing stereoselectivity with the catalyst have been investigated and delineated. Under optimal conditions, the catalyst gives >95% e.e. and 98:2 exo:endo ratio in the cycloaddition of methacrolein and cyclopentadiene.     

Theoretical Studies on the Diastereoselectivity in the Lewis Acid Catalyzed Carbonyl?Ene Reaction: A Fundamental Role of Electrostatic Interaction

Lewis acids affect reactivity, selectivity, and mechanism in the carbonyl‐ene reaction. The diastereoselectivity in the glyoxylate‐ene reaction depends on Lewis acids. While the SnCl₄‐promoted reaction can be achieved with a high level of anti‐selectivity, the use of Al reagents leads to a high syn‐selectivity. The origin of the Lewis acid dependency of the diastereoselectivity in the carbonyl? ene reaction of (E)‐but‐2‐ene with glyoxylate was theoretically studied (HF/6‐31G*) from the point of view of differences and similarities between the ene and the Diels–Alder reactions. Though it has been widely accepted that the endo‐preference would be less obvious in the ene reaction than in the Diels–Alder reaction, our ab initio molecular studies showed that the electrostatic interaction between carbonyl O‐atom lone pair and cationic allylic central C‐atom of ene component exists in the Lewis acid‐promoted carbonyl–ene reaction to affect the transition‐state conformation. It is illustrated that such an electrostatic interaction is essential to control the exo/endo‐selectivity, which provides the diastereoselectivity of the product in the transition state of the Lewis acid promoted carbonyl? ene 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 [HOMO_diene–LUMO_dienophile] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.     

Stereoselective Synthesis of Novel Diels–Alder Adducts of p-Substituted Methyl Thiocinnamates and Cyclopentadiene

This article describes the Diels–Alder reaction between methyl thiocinnamates, substituted at the para position by electron-donating and electron-withdrawing groups, with cyclopentadiene in the presence of catechol boron bromide (CBB) as a Lewis acid catalyst. The adduct configuration was confirmed by ¹H NMR coupling constants and single-crystal x-ray diffraction. Total endo stereoselectivity was observed in all reactions and was attributed to the effective secondary interaction between the boron atom and the incipient double bond in the norbonene resulting from the planar geometry of the catalyst. ¹³C NMR chemical shifts of the coordinated dienophile carbonyl carbons with CBB compared to those of the non coordinated thiocinammates suggest a strong complexation with the catalyst.     

Ab initio study of the effect of CH ··· O hydrogen bonding on the exo/endo stereoselectivity of Diels-Alder reactions of 2-substituted-1,3-dienes with sulfur dioxide

Ab initio calculations at the MP 2/6-31G *//HF /3-21G * level have been carried out to study Diels-Alder reactions of 2-substituted-1,3-dienes with sulfur dioxide. The CH ··· O electrostatic interaction detected in some of the transition structures located could be decisive in the control of the exo/endo stereoselectivity of this type of reaction. © 1996 John Wiley & Sons, Inc.     

Asymmetric hetero-Diels–Alder reaction of 1-alkyl-3-silyloxy-1,3-dienes with ethyl glyoxylate catalyzed by a chiral (salen)cobalt(II) complex

The hetero-Diels–Alder reactions of 1-alkyl-3-(tert-butyldimethylsilyl)oxy-1,3-butadienes with ethyl glyoxylate catalyzed by chiral salen–metal complexes have been studied. With a cobalt(II) complex as the catalyst, the reaction of 1-(2-benzyloxyethyl)-3-(tert-butyldimethylsilyl)oxy-1,3-butadiene with ethyl glyoxylate gave the Diels–Alder product in 75% isolated yield with the endo:exo ratio >99:1 and the enantiomeric excess ≥52%. The effects of temperature, catalyst and solvent are also discussed.     

An Enantioselective Inverse‐Electron‐Demand Imino Diels–Alder Reaction

The imino Diels–Alder reaction is an efficient method for the synthesis of aza‐heterocycles. While different stereo‐ and enantioselective inverse‐electron‐demand imino Diels–Alder (IEDIDA) reactions have been reported before, IEDIDA reactions including electron‐deficient dienes are unprecedented. The first enantioselective IEDIDA reaction between electron‐poor chromone dienes and cyclic imines, catalyzed by zinc/binol complexes is described. The novel reaction provides a facile entry to a natural product inspired collection of ring‐fused quinolizines including a potent modulator of mitosis.