6,6'-Substituent effect of BINOL in bis-titanium chiral Lewis acid catalyzed 1,3-dipolar cycloaddition of nitrones

By the accommodation of modified BINOLs as chiral ligands, enantioselectivities in the bis-titanium chiral Lewis acid catalyzed 1,3-dipolar cycloaddition of N-diphenylmethyl nitrones and methacrolein could be improved.     

Asymmetric 1,3-dipolar cycloaddition of chiral sulphinylethenes with 1-methyl-3-oxido-pyridinium and some nitrones

1,3-Dipolar cycloaddition of (R)-(+)-p-tolyl vinyl sulphoxide 1 with 1-methyl-3-oxidopyridinium 6 proceeded in a diastereoselective manner to afford the exo and endo cycloadducts 11a,b and 12a in 36%, 7% and 29% yield, respectively. The absolute configuration of 11a was determined by its transformation to (1S)-(−)-2-tropanol (−)-15. Attempts to the cycloaddition of the sulphinylethenes 17–19 with the pyridinium 6 were nsuccessful under several conditions. The reaction of the sulphoxide 20 with pyrroline 1-oxide 21 gave an inseparable mixture of products. The cycloaddition of 20 with 3,4,5,6-tetrahydropyridine 1-oxide22 afforded a mixture of four adducts in ca. 90% yield. High level of diastereoselectivity was achieved for the endo cycloaddition affording the adduct 23 in 33% isolated yield. The absolute configuration of 23 was confirmed by a single-crystal X-ray diffraction study. The stereochemical course of the reaction was discussed based on the absolute configuration of the products.     

Asymmetric 1,3-dipolar cycloadditions of nitrones and methacrolein catalyzed by chiral bis-titanium lewis acid: a dramatic effect of N-substituent on nitrone

Highly stereoselective 1,3-dipolar cycloadditions of methacrolein and nitrones could be realized by the use of bis-titanium chiral Lewis acid catalyst. Key to the success is the introduction of bulky N-substituent on nitrone to attenuate the undesired Lewis acid-nitrone complexation.     

Iron and ruthenium Lewis acid catalyzed asymmetric 1,3-dipolar cycloaddition reactions between nitrones and enals

The single coordination-site transition metal Lewis acids [CpM(BIPHOP-F)][SbF6] (M = Fe, Ru) catalyze the [3+2] dipolar cycloaddition reaction between reactive nitrones and alpha,beta-unsaturated aldehydes to give chiral isoxazolidines with ee values of 75 to >96%. The stereochemistry of the major enantiomer is consistent with an endo approach of the nitrone to the Calpha-Si-face of the enal in the s-trans conformation in the (R,R)-catalyst site. The absolute configuration is based on an X-ray structure determination.     

The 1,3-dipolar cycloaddition of adamantine-derived nitrones with maleimides

Abstract

Adamantane-derived aldo- and ketonitrones react with maleimides giving corresponding isoxazolidines. In the case of aldonitrones reactions proceed giving the diastereomeric mixtures. The ratio of isomers is changing during the reaction process due to the reversibility of the cycloaddition reaction. The cytotoxic and virus-inhibiting activity against influenza virus was investigated for selected adducts.     

1,3-dipolar cycloaddition of nitrones to sugar enlactones

It was found that 1,3-dipolar cycloaddition of nitrones derived from formaldehyde and acetaldehyde to sugar enlactones proceeds regio- and stereospecifically to afford anti - endo adducts.     

The effects of Lewis acid on the 1,3-dipolar cycloaddition reaction of C-arylaldonitrones with alkenes

The regio- and stereoselectivity of the 1,3-dipolar cycloaddition reactions of C-aryl-N-alkylaldonitrones (1a-e) with some alkenes were found to be affected significantly by the addition of Lewis acid. The rate of the reaction was also affected by adding the Lewis acid. In the reactions using allyl alcohol as a dipolarophile an addition of Lewis acid caused a remarkable acceleration of the reaction and a great change in the stereoselectivity. In the reactions using ethyl acrylate as a dipolarophile the regioselectivity was reversed whether the reaction was performed in the presence or the absence of Lewis acid; i.e. isoxazolidine-5-carboxylates were obtained mainly in the absence of Lewis acid although isoxazolidine-4-carboxylates were obtained mainly in the presence of Lewis acid. When the reaction of C,N-diarylaldonitrones (1k, 1m, 1n) with ethyl acrylate was carried out in the presence of Lewis acid, the cleavage of the N-O bond of the cycloadducts giving gamma-aminoalcohols was also observed besides a reverse phenomenon of regioselectivity.     

Understanding the role of the Lewis acid catalyst on the 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein: a DFT study

The Lewis acid (LA) catalyzed 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein has been studied using DFT calculations. Coordination of AlCl₃ to the acrolein oxygen atom produces a drastic change in the mechanism along the more favorable meta reactive channel. The process is characterized by a strong nucleophile/electrophile interaction allowing the formation of a zwitterionic intermediate, a Michael-type addition. The subsequent ring closure constitutes the rate-determining step. The energies obtained with the inclusion of solvent effect by means of the polarizable continuum model are in good agreement with experimental findings. Analysis of the global and local electrophilicity allows to explain correctly the reactivity and regioselectivity of the LA catalyzed cycloaddition.     

Asymmetric 1,3-dipolar cycloaddition reaction of α,β-unsaturated nitriles with nitrones catalyzed by chiral-at-metal rhodium or iridium complexes

The aqua complexes (S_M,R_C)-[(η⁵-C₅Me₅)M{(R)-Prophos}(H₂O)](SbF₆)₂ (M = Rh, Ir; (R)-Prophos = 1,2-bisdiphenylphosphino propane) catalyze the 1,3-dipolar cycloaddition reaction (DCR) of nitrones with α,β-unsaturated nitriles with low-to-moderate enantioselectivity. The involved catalysts [(η⁵-C₅Me₅)M{(R)-Prophos}(α,β-unsaturated nitrile)](SbF₆)₂, isolated as mixtures of the (S_M,R_C)- and (R_M,R_C)-diastereomers, have been fully characterized, and the molecular structure of the complexes (S_Rh,R_C)-[(η⁵-C₅Me₅)Rh{(R)-Prophos}(cis-2-pentenenitrile)](SbF₆)₂ and (S_Ir,R_C)-[(η⁵-C₅Me₅)Ir{(R)-Prophos}(acrylonitrile)](SbF₆)₂ has been determined by X-ray diffraction. The (R)-at-metal epimers isomerize to the (S)-at-metal counterparts. Diastereopure (S_M,R_C)-[(η⁵-C₅Me₅)M{(R)-Prophos}(α,β-unsaturated nitrile)](SbF₆)₂ complexes catalyze the above-mentioned DCR in a stoichiometric manner with up to 97% ee. The results make clear the influence of the metal configuration on the catalytic stereochemical outcome. The catalysts can be recycled without significant loss of either activity or selectivity.     

Targeted 1,3-dipolar cycloaddition with acrolein for cancer prodrug activation

Cytotoxic anticancer drugs used in chemotherapy are often antiproliferative agents that preferentially kill rapidly growing cancer cells. Their mechanism relies mainly on the enhanced proliferation rate of cancer cells and is not genuinely selective for cancer cells. Therefore, these drugs can also significantly affect healthy cells. Prodrug therapy provides an alternative approach using a less cytotoxic form of anticancer drug. It involves the synthesis of inactive drug derivatives which are converted to an active form inside the body and, preferably, only at the site of cancerous tissues, thereby reducing adverse drug reaction (ADR) events. Herein, we demonstrate a prodrug activation strategy by utilizing the reaction between aryl azide and endogenous acrolein. Since acrolein is generally overproduced by most cancer cells, we anticipate our strategy as a starting point for further applications in mouse models with various cancers. Furthermore, cancer drugs that have had therapeutic index challenges might be reconsidered for application by utilizing our strategy.

Prodrug activation strategy by utilizing the reaction between aryl azide and endogenous acrolein that is generally overproduced by cancer cells.     

Asymmetric 1,3-dipolar cycloaddition of nitrile oxides to chiral acryloyl esters bearing glucofuranose as auxiliary

Asymmetric 1,3-dipolar cydoaddition of nitrite oxides to an acryloyl ester (1) derived from 1,2:5,6-di-O-isopropylidene glucose (6) was studied. Solvent and temperature effect was discussed. The single diastereoisomer was isolated with high diastereoselective excess.     

The regiochemistry and stereochemistry of 1,3-dipolar cycloaddition of cyclic nitrones

A comparative study of the regio- and stereo-chemical behaviour of the 1,3-dipolar cycloaddition of a series of alkenes with 1-pyrroline 1-oxide and 2,3,4,5-tetrahydropyridine 1-oxide has been carried out. The high degree of both regio- and stereochemical control observed in these reactions has been explained in terms of frontier orbital interaction, steric factors, and secondary orbital interaction in the transition state. While most common alkenes (both mono- and 1,1-di-substituted) gave 2-substituted cycloadducts, highly polarized alkene dimethyl methylenemalonate afforded mainly regioisomeric 3-substituted cycloadduct. Significant secondary orbital interaction is observed with the non-conjugated substituents, hydroxymethyl and its derivatives.     

Tricyclic-isoxazolidine analogues via intramolecular 1,3-dipolar cycloaddition reactions of nitrones

The tricyclic-isoxazolidine analogues tetrahydrothiochromenoisoxazoles, hexahydroisoxazolequinolines and tetrahydroisoxazolepyranopyridines were prepared by an intramolecular 1,3-dipolar cycloaddition reaction of a nitrone with an alkene. For N-alkylated hexahydroisoxazolequinolines, reduction of the reaction time from two days to 40 min was achieved using microwave heating. The cyclization to form tetrahydroisoxazolepyranopyridines only proceeded when the alkene was substituted with an electron withdrawing group.     

Preparation and stereoselectivity of 1,3-dipolar cycloaddition ofD-glucose-derived nitrones to N-arylmaleimides

Summary Nitrones2 derived fromD-glucose oxime and benzaldehydes without employing any protection of hydroxyl group were isolated in pure state. The 1,3-dipolar cycloaddition of2 to N-arylmaleimides gave predominantly theanti isoxazolidines3 and was rationalized byZ/E isomerization of N-glycosylnitrones2. The structure and steric configuration of the products have been assigned on the basis of¹H- and¹³C-NMR spectroscopy. AM1 calculations of the nitrones and MM2 calculations of the adducts were performed.

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Darstellung und Stereoselektivität der 1,3-dipolaren Cycloaddition vonD-Glucose-abgeleiteten Nitronen an N-Arylmaleimiden

Zusammenfassung Die Nitrone2 wurden ausD-Glucoseoxim und Benzaldehyden ohne Schutz von Hydroxylgruppen in reinem Zustand erhalten. Die 1,3-dipolare Cycloaddition von2 an N-Arylmaleimiden ergab bevorzugt dieanti-Isoxazolidine3; dies wurde über eineZ/E-Isomerisierung der N-Glycosylnitrone2 rationalisiert. Struktur und Stereochemie wurden auf Basis von¹H- und¹³C-NMR-Spektroskopie ermittelt. Außerdem wurden AM1-Berechnungen an den Nitronen und MM2-Rechnungen an den Addukten ausgeführt.

     

Evaluation of chiral bidentate ligand–metal complexes in asymmetric 1,3-dipolar cycloaddition reaction of nitrones with 3-alkenoyl-2-oxazolidinones

For evaluation of a chiral C₂-symmetric bis(oxazoline) ligand, its Lewis acid complexes-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of nitrones with electron-deficient dipolarophiles, 3-(2-alkenoyl)-1,3-oxazolidin-2-ones, have been investigated and it was found that the cycloadditions using a Cu(II)-bis(oxazoline) complex under optimized reaction conditions induced extremely high enantioselectivity.     

Diastereoselective 1,3-dipolar cycloaddition of pyrylium ylides with chiral enamides

Chiral enamides 5f-i were found to react with pyrylium ylides to give cycloadducts 6d-i in good yields with an excellent level of stereoselectivity. The chiral auxiliary was successfully removed on hydrogenolysis of compound 6f in continuous flow (H-Cube) resulting in the first asymmetric synthesis of complex amine 8.     

Asymmetric inverse electron-demand 1,3-dipolar cycloaddition of ynolates with a chiral nitrone derived from l-serine leading to β-amino acid derivatives

Asymmetric 1,3-dipolar cycloaddition of lithium ynolates with a nitrone derived from Garner’s aldehyde is described. The cycloadducts, 5-isoxazolidinones, were obtained in good yields with high diastereoselectivity. Alkylation of the intermediates, the 5-isoxazolidinone enolates, was also achieved with high selectivity, the products of which were converted into the enantiomerically pure β-amino acids, β-lactams, and γ-lactams. In our cycloaddition, lithium ynolates proved to be much better as nucleophiles than lithium enolates.     

Diastereoselectivity-switchable and highly enantioselective 1,3-dipolar cycloaddition of nitrones to alkylidene malonates

Trisoxazoline 1/Co(ClO(4))(2).6H(2)O catalyzed the 1,3-cycloaddition between nitrones 3 with alkylidene malonates 2 at 0 degrees C to give the isoxazolidines with both high enantioselectivity and high exo selectivity. However, when the temperature was lowered from 0 to -40 degrees C, the same cycloaddition afforded endo isomers as the major products with good to high enantioselectivity. A mechanism is provided.     

Preparation and stereoselectivity of 1,3-dipolar cycloaddition of C-glycosyl nitrones to N-arylmaleimides

Summary The cycloaddition of 3-hydroxyglycosyl-N-methylnitrone (1) to N-arylmaleimides gave thesyn isoxazolidines6, whereas 3-acetoxyglycosyl-N-methylnitrone (2) afforded theanti isoxazolidines8 and10. The formation of6 was rationalized by anexo attack, stereoelectronically preferred through the hydrogen bond between the pentose hydroxyl group and one of the carbonyl groups of N-arylmaleimide. The sterically preferredendo attack avoiding the repulsions between N-arylmaleimide and sugar moiety was proposed for addition of2. The structure and steric configuration of the products have been assigned on the basis of¹H- and¹³C-NMR spectroscopy, mainly by nuclear Overhauser effect difference spectroscopy. AM1 calculations of the nitrones and MM2 calculations of the adducts were performed.

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Darstellung und Stereoselektivität der 1,3-dipolaren Cycloaddition von C-Glycosyl-Nitronen an N-Arylmaleimiden

Zusammenfassung Die Cycloaddition von 3-Hydroxyglycosyl-N-methylnitron (1) an N-Arylmaleimide gab diesyn-Isoxazolidine6, mit 3-Acetoxyglycosyl-N-methylnitron (2) wurden hingegen dieanti-Isoxazolidine8 und10 erhalten. Die Bildung von6 wurde mit einemexo-Angriff erklärt, der stereoelektronisch wegen einer Wasserstoffbrückenbindung zwischen der Hydroxylgruppe der Pentose und einer Carbonylgruppe des N-Arylmaleimides bevorzugt wird. Für die Addition von2 wurde ein sterisch bevorzugterendo-Angriff vorgeschlagen, da dabei ungünstige Wechselwirkungen zwischen der N-Arylmaleimid- und der Zuckereinheit vermieden werden. Die Struktur und Stereochemie der Produkte wurde mittels¹H- und¹³C-NMR unter Verwendung von NOE-Differenzmessungen ermittelt. Es wurden auch AM1-Rechnungen für die Nitrone und MM2-Rechnungen für die Addukte durchgeführt.

     

Asymmetric Mukaiyama aldol reaction of silyl enol ethers with aldehydes using a polymer-supported chiral Lewis acid catalyst

Chiral N-sulfonylated α-amino acid monomer (5) derived from (S)-tryptophan was copolymerized with styrene and divinylbenzene under radical polymerization conditions to give a polymer-supported N-sulfonyl-(S)-tryptophan (6). Treatment of the polymer-supported chiral ligand with 3,5-bis(trifluoromethyl)phenyl boron dichloride afforded a polymeric Lewis acid catalyst (16) effective for asymmetric Mukaiyama aldol reaction of silyl enol ethers and aldehydes. Various aldehydes were allowed to react with silyl enol ethers in the presence of the polymeric chiral Lewis acid to give the corresponding aldol adducts in high yield with high levels of enantioselectivity.