Efficient Dienophiles Research Articles

Advances in Tetrazine Bioorthogonal Chemistry Driven by the Synthesis of Novel Tetrazines and Dienophiles.

Bioorthogonal chemistry has found increased application in living systems over the past decade. In particular, tetrazine bioorthogonal chemistry has become a powerful tool for imaging, detection, and diagnostic purposes, as reflected in the increased number of examples reported in the literature. The popularity of tetrazine ligations are likely due to rapid and tunable kinetics, the existence of high quality fluorogenic probes, and the selectivity of reaction. In this Account, we summarize our recent efforts to advance tetrazine bioorthogonal chemistry through improvements in synthetic methodology, with an emphasis on developing new routes to tetrazines and expanding the range of useful dienophiles. These efforts have removed specific barriers that previously limited tetrazine ligations and have broadened their potential applications. Among other advances, this Account describes how our group discovered new methodology for tetrazine synthesis by developing a Lewis acid-promoted, one-pot method for generating diverse symmetric and asymmetric alkyl tetrazines with functional substituents in satisfactory yields. We attached these tetrazines to microelectrodes and succeeded in controlling tetrazine ligation by changing the redox state of the reactants. Using this electrochemical control process, we were able to modify an electrode surface with redox probes and enzymes in a site-selective fashion. This Account also describes how our group improved the ability of tetrazines to act as fluorogenic probes by developing a novel elimination-Heck cascade reaction to synthesize alkenyl tetrazine derivatives. In this approach, tetrazine was conjugated to fluorophores to produce strongly quenched probes that, after bioorthogonal reaction, are "turned on" to enhance fluorescence, in many cases by >100-fold. These probes have allowed no-wash fluorescence imaging in living cells and intact animals. Finally, this Account reviews our efforts to expand the range of dienophile substrates to make tetrazine bioorthogonal chemistry compatible with specific biochemical and biomedical applications. We found that methylcyclopropene is sufficiently stable and reactive in the biological milieu to act as an efficient dienophile. The small size of the reactive tag minimizes steric hindrance, allowing cyclopropene to serve as a metabolic reporter group to reveal biological dynamics and function. We also used norbornadiene derivatives as strained dienophiles to undergo tetrazine-mediated transfer (TMT) reactions involving tetrazine ligation followed by a retro-Diels-Alder process. This TMT reaction generates a pair of nonligating products. Using nucleic acid-templated chemistry, we have combined the TMT reaction with our fluorogenic tetrazine probes to detect endogenous oncogenic microRNA at picomolar concentrations. In a further display of dienophile versatility, we used a novel vinyl ether to cage a near-infrared fluorophore in a nonfluorescent form. Then we opened the cage in a "click to release" tetrazine bioorthogonal reaction, restoring the fluorescent form of the fluorophore. Combining this label with a corresponding nucleic acid probe allowed fluorogenic detection of target mRNA. In summary, this Account describes improvements in tetrazine and dienophile synthesis and application to advance tetrazine bioorthogonal chemistry. These advances have further enabled application of tetrazine ligation chemistry, not only in fundamental research but also in diagnostic studies.

ChemInform Abstract: Cu(I)‐Catalyzed Asymmetric Multicomponent Cascade Inverse Electron‐Demand Aza‐Diels—Alder/Nucleophilic Addition/Ring‐Opening Reaction Involving 2‐Methoxyfurans as Efficient Dienophiles.

AbstractVarious tetrahydropyridazines containing a γ‐hydroxyl ester moiety are prepared by an unprecedented asymmetric three‐component cascade reaction from 2‐alkoxyfurans, hydrazones and water.

Cu(I)-Catalyzed Asymmetric Multicomponent Cascade Inverse Electron-Demand Aza-Diels-Alder/Nucleophilic Addition/Ring-Opening Reaction Involving 2-Methoxyfurans as Efficient Dienophiles.

An unprecedented multicomponent cascade asymmetric inverse-electron-demand Diels-Alder/nucleophilic addition/ring-opening reaction involving 2-methoxyfurans as efficient dienophiles was successfully developed with Cu(I)/(t)Bu-Box complex as the catalyst. A diverse array of tetrahydropyridazines containing unexpectedly stable γ-hydroxyl ester moiety was obtained in generally good yield with exclusive regioselectivity and excellent stereoselectivity.

Facile access to boryltetralins and borylnaphthalenes via a cycloaddition using o-quinodimethanes

Borylalkenes are found to serve as efficient dienophiles in a cycloaddition reaction with o-quinodimethanes, giving diverse boryltetralins, which are convertible into borylnaphthalenes via an oxidative aromatization.

Benzofurans as Efficient Dienophiles in Normal Electron Demand [4 + 2] Cycloadditions

Dearomatization of electron-poor benzofurans is possible through involvement of the aromatic 2,3-carbon-carbon double bond as dienophile in normal electron demand [4 + 2] cycloadditions. The tricyclic heterocycles thereby produced bear a quaternary center at the cis ring junction, a feature of many alkaloids such as morphine, galanthamine, or lunaridine. The products arising from the reaction have been shown to depend on different factors among which the type of the electron-withdrawing substituent of the benzofuran, the nature of the reacting diene, and the method of activation. In the presence of all-carbon dienes, the reaction yields the expected Diels-Alder adducts. When thermal activation is insufficient, a biactivation associating zinc chloride catalysis and high pressure is required to generate the cycloadducts in good yields and high stereoselectivities, for instance, when cyclohexadiene is involved in the process. The use of more functionalized dienes, such as those bearing alkoxy or silyloxy substituents, also shows the limits of the thermal activation, and hyperbaric conditions are, in this case, well-suited. The involvement of Danishefsky's diene induces a competition in the site of reactivity. The aromatic 2,3-carbon-carbon double bond is unambiguously the most reactive dienophile, and the 3-carbonyl unit becomes a competitive site of reactivity with benzofurans bearing substituents prone to heterocyloaddition, in particular under Lewis acid activation. The sequential involvement of both the aromatic double bond and the carbonyl moiety as dienophiles is then possible by using an excess of diene under high-pressure activation. In line with the experimental results, DFT computations suggest that the Diels-Alder process involving the aromatic double bond is preferred over the hetero-Diels-Alder route through an asynchronous concerted transition state. However, Lewis acid catalysis appears to favor the heterocycloaddition pathway through a stepwise mechanism in some cases.

2‐Alkenoyl Pyridine N‐Oxides, Highly Efficient Dienophiles for the Enantioselective Cu(II)—Bis(oxazoline) Catalyzed Diels—Alder Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

2-Alkenoyl Pyridine N-Oxides, Highly Efficient Dienophiles for the Enantioselective Cu(II)−Bis(oxazoline) Catalyzed Diels−Alder Reaction

2-Alkenoyl pyridine N-oxides are introduced as a new kind of efficient dienophiles for the Cu(II)-bis(oxazoline) (BOX) catalyzed enantioselective Diels-Alder reaction affording higher reactivity and enantioselectivity (ee's up to 96%) than the corresponding nonoxidized 2-alkenoyl pyridines.

Synthetic Applications of α-Fluoroalkylated Enones. 1. Use as Dienophiles in Diels−Alder Cycloadditions

Beta-fluoroalkylated enones are efficient dienophiles in Diels-Alder cycloadditions to prepare various fluorinated cylic compounds. However, the presence of the fluoroalkyl moiety modifies the reactivity and the selectivity of these cycloadditions.

2-Nitrofurans as dienophiles in Diels–Alder reactions

α-Nitrofuran derivatives are studied in Diels–Alder reactions under thermal conditions. In contrast to α-acylfurans, they proved to be efficient dienophiles.

1‐Triflylpyrroles as Efficient Dienophiles in Normal Electron Demand [4 + 2] Cycloaddition Reactions under Pressure.

AbstractFor Abstract see ChemInform Abstract in Full Text.

1-Triflylpyrroles as efficient dienophiles in normal electron demand [4+2] cycloaddition reactions under pressure

1-Triflylpyrroles bearing acetyl group(s) on position 3, or 2 and 4, are efficient dienophiles in normal electron demand Diels-Alder reactions activated by high pressures and Lewis acids.

Alkynylboronic Esters as Efficient Dienophiles in Cobalt‐Catalyzed Diels—Alder Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Alkynylboronic esters as efficient dienophiles in cobalt-catalyzed Diels-Alder reactions.

Versatile building blocks with a dihydroaromatic vinylic boron substructure can be generated efficiently by cobalt-catalyzed Diels–Alder reactions and used in Suzuki coupling reactions for the synthesis of functionalized polycyclic compounds (see scheme).

Recoverable chiral sulfoxide: remote asymmetric induction in Lewis acid-promoted Diels–Alder reaction of chiral sulfinyl-substituted pyrrolyl α,β-unsaturated enones

1-[2-(p-Tolylsulfinyl)]pyrrolyl α,β-unsaturated enones served as efficient dienophiles in the Diels–Alder reaction, where the use of aluminium chloride or a lanthanide triflate effected the cycloaddition with cyclopentadiene, affording the endo adduct with high diastereoselectivity. In particular, for the sulfinyl dienophile, the chiral auxiliary (i.e. the sulfinyl pyrrole) was recovered after use without any loss of optical purity.

Eu(fod) 3 and SnCl 4-catalyzed heterocycloadditions of O-silyl enol ethers deriving from cyclic ketones

O-t-Butyldimethylsilyl enol ethers deriving from simple cyclic ketones acted as efficient dienophiles in the Lewis acid-catalyzed heterocycloadditions with methyl benzylidenepyruvate 1. Good selectivities were observed with cyclohexanone derivatives. Using Eu(fod) 3, the dienophile 2b led to the expected endo adduct 3b (93–97%). When using SnCl 4, the major product (89–95%) was found to be the “abnormal” adduct 5b with a trans ring junction.

Remote Asymmetric Induction in Lewis Acid-Catalyzed Diels-Alder Reaction of .ALPHA.,.BETA.-Unsaturated Enones Having a Chiral Sulfinyl-Substituted, 5-Membered Aromatic Heterocycle.

Two types of chiral sulfoxides as Diels-Alder dienophiles were synthesized and high levels of diastereoselectivity were observed in cycloadditions. 2-Furyl and 2-thienyl α, β-enones, bearing a chiral sulfinyl group in the heterocycle, served as efficient dienophiles in Diels-Alder reactions, where the catalytic use of aluminium chloride or a lanthanide triflate effected the cycloaddition with cyclopentadiene affording the endo adduct with high diastereoselectivity, ranging from 91% to 98%.

Polyhalogenated heterocyclic compounds. Part 41. Cycloaddition reactions involving hexafluorobut-2-yne and 1,1,1,2,4,4,4-heptafluorobut-2-ene

Cycloadducts, formed by addition of hexafluorobut-2-yne, may be transformed into bis(trifluoromethyl)-benzene, -phenol and -furan derivatives. Tetrakis(trifluoromethyl)benzene may also be produced. Heptafluorobut-2-ene 2 is also a very efficient dienophile for reactions with cyclopentadiene and furan. Reaction of 2 with furan derivatives at elevated temperatures gives a very effective ‘one pot’ synthesis of 3,4-bis(trifluoromethyl)furan derivatives.

Chiral Sulfinylethenes as Efficient Dienophiles for Asymmetric Diels-Alder Reactions

Abstract An overview of our recent studies on asymmetric Diels-Alder reactions of chiral vinyl sulfoxides (= sulfinylethenes) is described. For the preparation of sulfinylethenes as Diels-Alder dienophiles, the Andersen method as well as a novel route by diastereoselective oxidation of exo-2-hydroxy-10-bornyl vinyl sulfides with 3-chloroperoxybenzoic acid (m-CPBA) is presented. The latter methodology has been successfully applied to a facile synthesis of two types of novel sulfoxides, i.e., α-sulfinylmaleate and α-sulfinylmaleimide derivatives. These sulfinyl dienophiles effect Diels-Alder reactions with a high degree of diastereoselectivity. Especially, the chiral α-sulfinylmaleimides readily react with Diels-Alder dienes of rather low reactivity, such as furan, to give the corresponding cycloadducts under conventional conditions. Applications of these asymmetric Diels-Alder reactions to natural product synthesis are also described.

Phenylsylfonyl-substituted 5-alkoxy-2(5H)-furanones; a new class of highly reactive chiral dienophiles.

The synthesis of enantiomerically pure (5S)-5-( d-menthyloxy)-4-(phenylsulfonyl)-2(5H)-furanone ( 4 ) and the application of 4 as efficient dienophile in Diels-Alder reactions under mild conditions with enantio-selectivities > 98% e.e. are described.

Capto-dative substituent effects. 12 1 - New ketene equivalents for diels-alder cycloadditions

We describe the use of “capto-dative” olefins 1 as novel ketene equivalents which behave as efficient dienophiles in the Diels-Alder process.