Cycloaddition Of Nitrones Research Articles

Utilization of electron-donating α,β-unsaturated oximes: regioselective inverse 1,3-dipolar cycloaddition of nitrones.

The cycloaddition of nitrones with α,β-unsaturated carbonyl compounds (enones) afforded predominantly 4-acylisoxazolidines, whereas the cycloaddition of the corresponding oximes afforded 5-iminoisoxazolidines. This inverse regioselection is due to HOMO activation by the oxime functionality.

Chiral N,N'-dioxide/Co(ii)-promoted asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones.

A chiral N,N'-dioxide/Co(BF4)2·6H2O complex catalytic system has been developed to efficiently catalyze the asymmetric 1,3-dipolar cycloaddition of nitrones with methyleneindolinones. The corresponding chiral multisubstituted spiroisoxazolidines with three contiguous quaternary-tertiary stereocenters were obtained in moderate to high yields with excellent dr and ee values (up to 97% yield, >19 : 1 dr and 98% ee).

Toward the Synthesis of (‒)-Codeine by Chiral Auxiliary-Mediated Nitrone Cycloaddition

Toward the Synthesis of (‒)-Codeine by Chiral Auxiliary-Mediated Nitrone Cycloaddition

1,3-Dipolar [3+2] cycloaddition reactions of N,C,C-trisubstituted nitrones with ring-acceptor methylenecyclopropanes: a computational study.

Background1,3-Dipolar [3 + 2]-cycloaddition of nitrones to the carbon–carbon double bonds of methylenecyclopropanes yields a mixture of regioisomeric 4- and 5-isoxazolidines. The mechanisms of the reactions of N,C,C-trisubstituted nitrones with ring acceptor substituted dimethyl methylenecyclopropanes-1,2-dicarboxylate and aryl methylidene cyclopropanes-1,1-dicarboxylate have been investigated with the Becke 3-Parameter Lee–Yang–Par exchange–correlation functional, a Hartree–Fock DFT hybrid functional, to delineate the factors responsible for the regioselectivity of these class of reactions.FindingsThe energetics of the reaction of the phenyl-substituted nitrone with unsubstituted methylenecyclopropane indicate that the formation of the 5-spirocyclopropane is favored over the 4-spirocyclopropane kinetically and thermodynamically. However, the energetics of the reaction of the same phenyl nitrone with vicinal ester (–CO2CH3)-substituted methylenecyclopropane show an inversion in the regioselectivity favoring the formation of the 4-regioisomer over the 5-regioisomer. For the reactions of N,C,C-trisubstituted nitrone with vicinal ester (–CO2CH3)-substituted methylenecyclopropane (–R1=H, –R2=Ph and –R1=CH3 and –R2=CO2CH3) and geminal ester (–CO2CH3)-substituted methylenecyclopropane (R3=H, R4=H; R3=OCH3, R4=CH3; and R3=H, R4=Cl), the energetics indicate that the 5-spirocyclopropane is favored over the 4-spirocyclopropane. The calculations also indicate that electron-donating groups increase regioselectivity of the 5-regioisomers over the 4-regioisomers.ConclusionThe regioselectivity of these reactions is determined by both electronic and steric factors. The pathways with the lower activation barrier leads to the more stable regioisomer in all cases, implying that the pathways that are kinetically favored are also thermodynamically favored. However, it is also clear from the energetics that these reactions are not reversible and are therefore under kinetic control. Therefore the selectivity of the reactions is governed solely by the difference in activation barriers leading to the two isomers and not in any way by the thermodynamic stability of the isomers formed.

ChemInform Abstract: Diastereoselective Synthesis of Novel Tetra‐ and Pentacyclic Annulated Coumarino‐δ‐sultam Pyrrolidine, Pyrrolizidine, Pyrrolothiazole and Isoxazolidine Derivatives via Intramolecular 1,3‐Dipolar Cycloadditions.

A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of nitrones or azomethine ylides is described. These highly functionalized polycyclic scaffolds were obtained with high diastereoselectivity in high yields via condensation of the initially prepared coumarin-based bifunctional starting materials with sarcosine or N-phenylglycine, L-proline or L-4-thiazolidinecarboxylic acid, and methyl or benzylhydroxylamine. The proof of the structures relies on analytical investigation and X-ray crystallography.

Copper(I)‐Catalyzed Asymmetric 1,3‐Dipolar [3+4] Cycloaddition of Nitrones with Azoalkenes

AbstractThe first copper(I)‐catalyzed asymmetric 1,3‐dipolar [3+4] cycloaddition of nitrones with azoalkenes has been developed, affording a variety of biologically important 1,2,4,5‐oxatriazepane derivatives in good yields with exclusive regioselectivities and excellent enantioselectivities.magnified image

Synthesis and chemical transformations of six/six-membered bicyclic nitroso acetals

A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated six-membered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of six-membered cyclic nitronates with donor-acceptor cyclopropanes. Some chemical transformations and conformational preferability of the obtained nitroso acetals are discussed.

How Dirhodium Catalyst Controls the Enantioselectivity of [3 + 2]-Cycloaddition between Nitrone and Vinyldiazoacetate: A Density Functional Theory Study.

The origin of enantioselectivity in the dirhodium-catalyzed [3 + 2]-cycloaddition of nitrone and vinyldiazoacetate has been investigated using dispersion-corrected density functional theory. Taking a more realistic account of bulky ligands in models of the dirhodium catalyst when investigating its catalytic behavior is crucial for describing the effects resulting from a high level of asymmetric induction. More than one active site can be located and the extra reactivity is provided by an electron-donation interaction between the substrate and an additional Rh2L4 catalyst.

1,3-Dipolar cycloaddition of a cyclic nitrone derived from 2-deoxy-D-ribose to α,β-unsaturated lactones: An entry to carbapenem antibiotics

1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to α,β-unsaturated γ- and δ-lactones were investigated. Cycloadducts obtained from δ-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to β-lactam ring formation by using Mukaiyama's salt. Cycloadducts from γ-lactones subjected to the same reaction sequence undergo β-elimination of a water molecule to provide pyrrolidine-substituted unsaturated γ-lactones.

Structural Manipulation of Ruthenium(II) Polypyridine Nitrone Complexes to Generate Phosphorogenic Bioorthogonal Reagents for Selective Cellular Labeling

We report a new class of ruthenium(II) polypyridine complexes functionalized with a nitrone group as phosphorogenic bioorthogonal probes. These complexes were very weakly emissive owing to rapid C=N isomerization of the nitrone moiety, but exhibited significant emission enhancement upon strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction with bicyclo[6.1.0]nonyne (BCN)-modified substrates. The modification of nitrone with a dicationic ruthenium(II) polypyridine unit at the α-C-position and a phenyl ring at the N-position led to remarkably accelerated reaction kinetics, which are substantially greater (up to ≈278 fold) than those of other acyclic nitrone-BCN systems. Interestingly, the complexes achieved specific cell membrane/cytosol staining upon specific labeling of an exogenous substrate, BCN-modified decane (BCN-C10), in live cells. Importantly, the in situ generation of the more lipophilic isoxazoline adduct in the cytoplasm resulted in increased cytotoxicity, highlighting a novel approach to apply the SPANC labeling technique in drug activation.

Dual Strain-Promoted Alkyne–Nitrone Cycloadditions for Simultaneous Labeling of Bacterial Peptidoglycans

Bioorthogonal chemistry has been applied to study a multitude of biological processes in complex environments through incorporation and detection of small functional groups. However, few reactions are known to be compatible with each other to allow for studies of more than one biomolecule simultaneously. Here we describe a dual labeling method wherein two stereoelectronically contrasting nitrone tags are incorporated into bacteria peptidoglycan and detected via strain-promoted alkyne-nitrone cycloaddition (SPANC) simultaneously. Furthermore, we show orthogonality with the azide functionality broadening the potential for simultaneous biomolecular target labeling in less accommodating metabolic pathways. We also demonstrate the simultaneous labeling of two different food-associated bacteria, L. innocua (a model for the food-born pathogen L. monocytogenes) and L. lactis (a fermentation bacterium). The ability to monitor multiple processes and even multiple organisms concurrently through nitrone/nitrone or nitrone/azide incorporation strengthens the current bioorthogonal toolbox and gives rise to robust duplex labeling of organisms to potentiate the studies of rapid biological phenomena.

ChemInform Abstract: Silyl Nitronate Cycloadditions Catalyzed by Cu(II)‐Bisoxazoline.

AbstractThe 1,3‐dipolar cycloaddition of silyl nitronates (II) with α,β‐unsaturated carboxamides (III) and (V) affords chiral isoxazolines (IV) and (VI), resp., in high yields, high enantioselectivities, and complete diastereoselectivities.

ChemInform Abstract: Synthesis of SF5‐Substituted Isoxazolidines Using 1,3‐Dipolar Cycloaddition Reactions of Nitrones with Pentafluorosulfanyl Acrylic Esters and Amides.

ChemInformVolume 47, Issue 5 Heterocyclic Compounds ChemInform Abstract: Synthesis of SF5-Substituted Isoxazolidines Using 1,3-Dipolar Cycloaddition Reactions of Nitrones with Pentafluorosulfanyl Acrylic Esters and Amides. Ewelina Falkowska, Ewelina Falkowska INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorMathieu Y. Laurent, Mathieu Y. Laurent INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorVincent Tognetti, Vincent Tognetti INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorLaurent Joubert, Laurent Joubert INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorPhilippe Jubault, Philippe Jubault INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorJean-Philippe Bouillon, Jean-Philippe Bouillon INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorXavier Pannecoucke, Xavier Pannecoucke INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this author Ewelina Falkowska, Ewelina Falkowska INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorMathieu Y. Laurent, Mathieu Y. Laurent INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorVincent Tognetti, Vincent Tognetti INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorLaurent Joubert, Laurent Joubert INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorPhilippe Jubault, Philippe Jubault INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorJean-Philippe Bouillon, Jean-Philippe Bouillon INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this authorXavier Pannecoucke, Xavier Pannecoucke INSA Rouen, CNRS UMR, Univ. Rouen, F-76821 Mont Saint Aignan, Fr.Search for more papers by this author First published: 14 January 2016 https://doi.org/10.1002/chin.201605150Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue5January, 2016 RelatedInformation

Theoretical investigations toward the [3 + 2]-dipolar cycloadditions of nitrones with vinyldiazoacetates catalyzed by Rh2(R-TPCP)4: mechanism and enantioselectivity

The mechanism of Rh2(R-TPCP)4-catalyzed [3 + 2]-dipolar cycloadditions between vinyldiazoacetate and nitrone to form 2,5-dihydroisoxazole has been studied by ONIOM methodology calculations including density functional theory and PM6 theory.

A theoretical study of the mechanism and selectivity of the intramolecular 1,3-dipolar cycloaddition reaction of the nitrone–alkene derived from 2-allylthiobenzaldehyde for the synthesis of tricyclic isoxazolidines

A computational study of the mechanism as well as the regio- and stereoselectivities of the intramolecular 1,3-dipolar cycloaddition (IMDC) of nitrone–alkene 1, derived from 2-allylthiobenzaldehyde, has been carried out using DFT methods at the MPWB1K/6-31G(d,p) level of theory. The four possible pathways, fused and bridged regioisomeric modes, and the two stereoisomeric approaches endo and exo for the IMDC reaction are analyzed and discussed. Analysis of the potential energy surface showed that this IMDC reaction kinetically favors formation of the isoxazolidine generated from the fused-endo pathway. The obtained results corroborate very well with the published experimental data. Analysis of TS geometries and bond order indicate that these IMDC reactions proceeded through a one-step synchronous mechanism for the fused modes and is asynchronous for the bridged modes.

Regiochemical and Stereochemical Studies of the Intramolecular Dipolar Cycloaddition of Nitrones Derived from Quaternary Aldehydes

Three aldehydes each with a quaternary α-carbon stereocentre bearing an alkenyl, a phenyl, and a methyl ester group were treated with N-methylhydroxylamine. In each case bicyclic isoxazolidine products were formed by condensation to give intermediate nitrones that undergo intramolecular dipolar cycloaddition. The stereoselectivity was influenced by the α-carbonyl substituent, possibly by a hydrogen bond between CO and a nearby CH of the nitrone in the transition state (supported by DFT and X-ray studies), and the regioselectivity was affected by the length of the tether and by the presence of an ester on the alkene dipolarophile.

An Unprecedented Formal [5 + 2] Cycloaddition of Nitrones with o-Carboryne via Tandem [3 + 2] Cycloaddition/Oxygen Migration/Aromatization Sequence.

Heterocyclic skeletons are widespread among natural products as well as bioactive molecules. Cycloaddition reaction has created new opportunities to access heterocycles of great complexity due to its advantage of multiple bond formation in a single step. Here, we describe an unprecedented formal [5 + 2] cycloaddition of nitrone with o-carboryne to afford carborane-fused seven-membered heterocycles. Experimental and theoretical data suggest that a sequence of [3 + 2] cycloaddition, N-O bond cleavage, oxygen migration and rearomatization is involved in this unprecedented reaction. In this process, the nitrone moieties serve as five-atom coupling partners with both heteroatoms being incorporated into the framework of the final products. This new methodology also offers new insight into the chemistry of nitrones.

Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3‐Dipolar Cycloaddition of Nitrones to α,β‐Unsaturated Aldehydes

AbstractThe catalytic activity of a simple amino alcohol that contains a bulky super silyl group [i.e., tris(trimethylsilyl)silyl (TTMSS)] bonded to the oxygen atom at the γ‐position along with a primary amine moiety was examined in the enantioselective 1,3‐dipolar cycloaddition of nitrones to α,β‐unsaturated aldehydes. The organocatalyst successfully provided optically active isoxazolidines in good chemical yields (up to 86 %) with excellent diastereoselectivities (endo/exo, up to 96:4) and enantioselectivities (up to 97 % ee). Furthermore, the obtained isoxazolidines were easily converted into γ‐amino diols that contain three contiguous stereogenic centers.

ChemInform Abstract: Ru‐Catalyzed Redox‐Neutral Cleavage of the N—O Bond in Isoxazolidines: Isatogens to Pseudoindoxyls via a One‐Pot [3 + 2]‐Cycloaddition/N—O Cleavage.

Abstract1,3‐Dipolar cycloaddition of nitrones (I) and (IV) with alkenes affords intermediary isoxazolidines which undergo direct one‐pot Ru‐catalyzed redox‐neutral N—O bond cleavage to yield 2,2‐disubstituted pseudoindoxyls.

ChemInform Abstract: Diastereoselective Construction of Highly Functionalized Tetrahydroquinolinoisoxazole Scaffolds via Intramolecular Nitrone Cycloaddition.

AbstractA diastereo‐ and regioselective construction of tetrahydroquinolinoisoxazoles (III) and (V) is achieved by reaction of Baylis—Hillman derivatives (I) and (IV) with N‐alkylhydroxylamine hydrochlorides.