We report herein the first examples of chiral phosphoric acid‐catalyzed enantioselective Diels–Alder reactions between 2‐trifluoroacetamido‐1,3‐dienes 1 and α,β‐unsaturated carbonyl compounds 2. ...Polysubstituted 1‐acetamido cyclohexenes 3 were formed in high yields with excellent diastereo‐ and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three‐component reaction of 1, 2 and ortho‐hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.
CPA‐catalyzed annulation of 2‐trifluoroacetamido‐1,3‐dienes with α,β‐unsaturated carbonyl compounds affords highly functionalized 1‐trifluoroacetamido cyclohex‐1‐ene derivatives 3 in high yields with excellent diastereo‐ and enantioselectivities. An asymmetric three‐component reaction of 1, 2 and ortho‐hydroxybenzhydryl alcohols 4 provides the densely functionalized hexahydroxanthenes with concurrent creation of five contiguous stereocenters.
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Two new thermoresponsive self‐healing polyurethanes (1DA1T and 1.5DA1T) based on the Diels–Alder (DA) reaction between furan and maleimide moieties are developed that use the shape‐memory effect to ...bring crack faces into intimate contact such that healing can take place. Unlike other self‐healing polymers, these polymers do not require external forces to close cracks but rather they use the shape‐memory effect to autonomously close the crack. Both polyurethanes have a stable polymer structure and comparable mechanical properties to commercial epoxies. A differential scanning calorimeter is employed to check the glass transition temperature of the polymers as well as the DA and retro‐DA (rDA) reaction temperatures. These DA and rDA reactions are confirmed with variable‐temperature proton nuclear magnetic resonance. Healing efficiency is calculated using a measurement of the failure load from compact tension testing. The results show that the shape‐memory effect can replace external forces to close two crack surfaces and the DA reaction can be repeatedly employed to heal the cracks.
Thermo‐responsive self‐healing polyurethanes that can be healed repeatedly without the application of external forces are developed. Instead, these polymers use the shape‐memory effect to autonomously bring the two crack surfaces together during the healing process.
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A clean reaction strategy based on thermally eliminating lactam bridges from a soluble acene precursor through a retro‐Diels–Alder reaction, led to the synthesis and characterization of a novel, ...stable, green crystalline 6,8,10,17,19,21‐hexaphenyl‐1.22,4.5,11.12,15.16‐tetrabenzononatwistacene. An analysis of the single crystal structure of the nonatwistacene indicates that this molecule is twisted at an angle of 25.44°.
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In this review, recent advances in asymmetric organocatalytic reactions carried out with variable amounts of water, from substoichiometric to a large excess (reaction medium), are discussed. We also ...summarize several proposed mechanisms for the different possibilities of the action of water both in the increased activity of the catalyst and in the asymmetric induction. Finally, the application of this catalytic methodology to the enantioselective synthesis of valuable compounds through enamine or iminium catalysis is presented.
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In this study, we attempted to explain why the substitution of a cyano group onto the 1‐azadiene moiety promotes N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine to undergo an intramolecular ...aza‐Diels–Alder reaction. Our M06‐2X study found that the intramolecular aza‐Diels–Alder reaction of N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine has an inverse electron demand. Therefore, the attachment of a cyano group to the diene moiety (1‐azadiene) makes the intramolecular aza‐Diels–Alder reaction feasible. Moreover, the intramolecular aza‐Diels–Alder reaction of N‐(2,3‐diphenylallylidene)pent‐4‐en‐1‐amine was found to be a kinetically controlled reaction.
In this study, the frontier molecular orbital theory was found to be not a useful tool to explain the electron demand of an intramolecular aza‐Diels–Alder reaction. Therefore, the local electrophilicity, a local reactivity descriptor derived from the conceptual density functional theory, was used to explain such electron demand.
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Although the Diels–Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust ...approach that combines various amines regioselectively with 4,6‐dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through 4+2 cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these—the complex amaryllidaceae alkaloid gracilamine—affording the shortest route to date in terms of linear step count.
Pyrone‐technics: A simple, robust, and readily modifiable strategy involving 4+2/retro‐4+2/hydrolysis cascade sequences generates a range of indolines and hydroindolines from 4,6‐dichloropyrone and appropriate amines. A 10 step synthesis was achieved of a ketone previously accessed in 15 steps, thereby accomplishing the shortest formal total synthesis of the alkaloid gracilamine. Teoc=2‐(trimethylsilyl)ethoxycarbonyl.
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Click reactions have the potential to greatly facilitate the development of drug delivery systems and biomaterials. These reactions proceed under mild conditions, give high yields, ...and form only inoffensive by-products. The Diels–Alder cycloaddition is one of the click reactions that do not require any metal catalyst; it is one of the most useful reactions in synthetic organic chemistry and material design. Herein, we highlight possible applications of the Diels–Alder reaction in pharmaceutics and biomedical engineering. Particular focus is placed on the synthesis of polymers and dendrimers for drug delivery, the preparation of functionalized surfaces, bioconjugation techniques, and applications of the Diels–Alder reaction in nanotechnology. Moreover, applications of the reaction for the preparation of hydrogels for drug delivery and tissue engineering are reviewed. A general introduction to the Diels–Alder reaction is presented, along with a discussion of potential pitfalls and challenges. At the end of the article, we provide a set of tools that may facilitate the application of the Diels–Alder reaction to solve important pharmaceutical or biomedical problems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We examined the catalytic activity of substituted thioureas in a series of Diels–Alder reactions and 1,3‐dipolar cycloadditions. The kinetic data reveal that the observed accelerations in the ...relative rates are more dependent on the thiourea substituents than on the reactants or solvent. Although the catalytic effectiveness is the strongest in noncoordinating, nonpolar solvents, such as cyclohexane, it is also present in highly coordinating polar solvents, such as water. In 1,3‐dipolar cycloadditions, the thiourea catalysts demonstrate only very moderate selectivity for reactions with inverse electron demand. Our experiments emphasize that both hydrophobic and polar interactions can co‐exist, making these catalysts active, even in highly coordinating solvents. This class of catalysts increases the reaction rates and endo‐selectivities of Diels–Alder reactions, in a similar manner to weak Lewis acids, without concomitant product inhibition.
Lowering of the transition‐state energy of a Diels–Alder model reaction between carbonyl dienophiles and cyclopentadiene promoted by hydrogen‐bond interactions is possible, even in water. In a similar manner to weak, neutral Lewis acids, catalytic amounts of electron‐poor thiourea derivatives accelerate these reactions through two‐point binding interactions that are enforced in aqueous media (see picture).
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In the field of lipid research, bioorthogonal chemistry has made the study of lipid uptake and processing in living systems possible, whilst minimising biological properties arising from detectable ...pendant groups. To allow the study of unsaturated free fatty acids in live cells, we here report the use of sterculic acid, a 1,2‐cyclopropene‐containing oleic acid analogue, as a bioorthogonal probe. We show that this lipid can be readily taken up by dendritic cells without toxic side effects, and that it can subsequently be visualised using an inverse electron‐demand Diels–Alder reaction with quenched tetrazine‐fluorophore conjugates. In addition, the lipid can be used to identify changes in protein oleoylation after immune cell activation. Finally, this reaction can be integrated into a multiplexed bioorthogonal reaction workflow by combining it with two sequential copper‐catalysed Huisgen ligation reactions. This allows for the study of multiple biomolecules in the cell simultaneously by multimodal confocal imaging.
This paper describes the use of a cyclopropene‐containing oleic acid analogue for studying live cell lipid uptake by dendritic cells. The minimal oleic acid analogue is incorporated into membranes and lipoproteins, which can be studied by live cell microscopy and lipoproteomics.
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2‐Pyrones with a chiral branched allylic silyl ether substituent underwent intramolecular Diels–Alder reactions with remarkably high π‐facial‐ and endo‐selectivities. The resulting diastereomerically ...and enantiomerically pure cycloadducts were transformed into the natural products (+)‐lycopladine A and (−)‐lycoposerramine R.
Highly efficient asymmetric intramolecular Diels–Alder reactions of 3‐substituted 2‐pyrones were combined with C3‐selective Stille cross‐coupling reactions in a tandem fashion. The resulting diastereomerically and enantiomerically pure cycloadducts were successfully converted into (+)‐lycopladine A and lycoposerramine R.
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