1,3-Dipolar cycloaddition approach to isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine

Isoxazole, isoxazoline and isoxazolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones derived from mono and disubstituted uracil-5-carbaldehydes and 2,4-dimethoxypyrimidine-5-carbaldehyde. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the heterocyclic ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed.     

Novel 1,3-dipolar cycloaddition reactions of calix[4]bis(spirodienones): synthesis of isoxazolidine derived macrocycles

Calix[4]bis(spirodienones) can perform as either 4π or 2π components in cycloaddition reactions with various carbo- and hetero-dienophiles and with 1,2-benzoquinones leading to the formation of highly functionalized macrocycles. In this Letter we report, highly regio- and stereoselective 1,3-dipolar cycloaddition reactions of a bis(spirodienone) derivative of calix[4]arene with nitrones that provide easy access to isoxazolidine derived macrocycles in excellent yields. These isoxazolidine derivatives can be considered as direct precursors of 1,3-amino alcohols.     

Synthese und Umwandlungen von Isoxazolidin-Nucleosiden

Synthesis and Transformations of Isoxazolidine-Nucleosides Reaction of the oxime 12 with formaldehyde, acetaldehyde or acetone in the presence of methacrylic acid methylester leads in a highly stereoselective 1,3 dipolar cycloaddition of the corresponding nitrones to the protected isoxazolidine ribosides 13, 14, 20, 21 and 26 (Scheme 1 and 2). Using a new, mild procedure to effect detriylation, the cycloaddition products were transformed into the alcohols 16–19 , 22–25 and 27 . Cleavage of a mixture of the glycosides 16 and 17 yielded the N-unsubstituted isoxazolidine 29 in 65% optical purity while the cleavage of 27 gave optically pure 28 . Alternatively, the isoxazolidine ribosides 13, 14, 16–18 and 26 were transformed via reductive cleavage of the isoxazolidine N-O bond and subsequent lactamization into the corresponding pyrrolidinone-ribosides 30, 33, 35, 42, 49 and 50 , the ribitolyl pyrrolidinones 31, 34, 36–39 and 43–46 (see Scheme 4) and the ribitolyl isoxazolidine 47 .     

Synthesis of Some Novel Class of Regioselective Spiro Isoxazolidine Derivatives via 1,3‐Dipolar Cycloaddition Reaction of N‐Benzyl‐C‐fluoro‐substituted Phenyl Nitrones in Ionic Liquid

Synthesis of some new class of regioselective spiro isoxazolidine derivatives have been described using N‐benzyl‐C‐fluoro substituted‐phenyl nitrones with new dipolarophiles via 1,3‐dipolar cycloaddition reaction in ionic liquid. The novel spiro cycloadducts found to exhibit good synthetic potentiality as they could be converted into synthetically more important spiro 1,3‐amino alcohols. Simple reaction methodology, noninvolvent of catalysts, good to excellent yields, and greener approaches are the important features noticed in this syntheses.     

1,3‐Dipolar Cycloaddition of Nitrones with Electron‐rich Alkenes Catalyzed by Yb(OTf)3

1,3‐Dipolar cycloaddition of nitrones with ethyl vinyl ether or 2,3‐dihydrofuran proceeds smoothly in the presence of a catalytic amount (10 mol%) of ytterbium triflate to afford isoxazolidines and dicyclic isoxazolidine respectively with good yields and high stereoselectivity.     

Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO₃ to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a–p in high yields via 1,3-dipolar cycloaddition reaction.     

Investigations on intramolecular 1,3-dipolar cycloadditions for the synthesis of isoxazolo-annulated pyrrolidines,piperidines and azepanes

Pyrrolidines, piperidines, and azepanes with annulated isoxazole, isoxazoline or isoxazolidine rings were prepared by intramolecular 1,3-dipolar cycloadditions of nitrones or nitrile oxides. The corresponding 1,3-dipoles were obtained from N-Boc-protected and N-allyl-, N-propargyl- or N-(3-butenyl)-substituted 2-aminoethanal or 3-aminopropanal.     

Catalytic highly enantioselective 1,3-dipolar cycloaddition reaction of nitrones with 3-alkenoyl-2-oxazolidinones by use of a bidentate chiral bis(imine) ligand–Cu(II) triflate complex

A copper(II) triflate complex with bidentate, chiral C₂-symmetric cyclohexane-1,2-bis[(2,6-dichlorophenylmethylene)amine] catalyzed the 1,3-dipolar cycloaddition reactions of nitrones with electron-deficient dipolarophiles, 3-(2-alkenoyl)-1,3-oxazolidin-2-ones to give isoxazolidine cycloadducts with extremely high endo- and enantioselectivities.     

Synthesis,structure and reactions of seco-steroids containing a medium-sized ring—IX : Reactions of Δ1(10)-unsaturated 5-oxo-5,10-seco-steroids with hydroxylamine and n-methylhydroxylamine

When treated with hydroxylamine or N-methylhydroxylamine, in the presence of proton donor catalysts, trans-Δ¹⁽¹⁰⁾-unsaturated 5-oxo-5,10-seco-steroids, such as 3 (but not the corresponding diastereomeric cis-compounds), are converted stereospecifically and in good yield to isoxazolidine derivatives (e.g. 4 and 13), resulting from transannular 1,3-dipolar addition of the intermediately formed oximes and nitrones to the trans-double bond in the cyclodecene ring moiety of the seco-steroid system. Reactions are described and physical evidence is presented which establish the constitution and configuration of the isoxazolidine-containing cycloaddition products, and the mechanistic and steric course of this transannular ring closure process is discussed.     

1,3-Dipolar Cycloaddition of Nitrones with 5-Methylenehydantoins: Synthesis and Transformation of New Spirohydantoin Derivatives

1,3-Dipolar cycloaddition of various acyclic nitrones with 5-methylenehydantoin derivatives afforded new chiral spiroadducts in good yields. All the spirohydantoins were obtained through a regio- and stereospecific pathway, and the spirocarbon atom was linked to the isoxazolidine oxygen atom. A representative example of the reduction of the spirohydantoin 8 with Zn/AcOH led to the substituted 1,3-aminoalcohol hydantoin 20.     

Phosphino Isoxazolidines: an Approach to Regio and Stereoselective Synthesis

Abstract

The 1,3-dipolar cycloaddition of nitrones to vinyl phosphorus derivatives, mainly phosphines and their oxides and sulfides, has been studied. The cycloaddition to chiral racemic phosphine oxides and sulfides gives adducts with considerable diastereofacial selectivity. The transition state model for the cycloaddition is discussed.     

Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the Preparation of β3‐Oligopeptides by Iterative α‐Keto Acid?Hydroxylamine (KAHA) Ligations

A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of β³‐oligopeptides via α‐keto acid? hydroxylamine (KAHA) ligation is presented. This one‐pot synthetic method utilizes in situ generated nitrones bearing gulose‐derived chiral auxiliaries for the asymmetric 1,3‐dipolar cycloaddition with methyl 2‐methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers bearing diverse side chains (proteinogenic and non‐proteinogenic) can be synthesized in either configuration (like‐ and unlike‐configured). The scalable and enantioselective synthesis of the isoxazolidine monomers enables the use of the synthesis of β³‐oligopeptides via iterative α‐keto acid? hydroxylamine (KAHA) ligation.     

Regioselective synthesis of some isoxazolines and isoxazolidines bearing caprolactam moiety

Isoxazoline and isoxazolidine series were obtained by the reactions of aromatic aldonitrones and nitrile oxides with N-vinyl caprolactam via regioselective 1,3-dipolar cycloadditions that yield only 5-caprolactam-substituted regioisomers in moderate yields. The cycloaddition reactions were optimized using different conditions. The utilized one for the transformation of nitrile oxides to isoxazoles is triethylamine at room temperature and the best protocol have been found for the transformation of nitrones to N-methyl isoxazolidines is silver acetate in refluxing xylene. The structural identification of target compounds was established by IR, nuclear magnetic resonance (NMR), high resolution mass spectrometry (HRMS) spectra, and X-ray diffraction analyses.     

Intramolecular 1,3-dipolar nitrone and nitrile oxide cycloaddition of 2- and 4-O-allyl and propargyl glucose derivatives: a versatile approach to chiral cyclic ether fused isoxazolidines, isoxazolines and isoxazoles

2-O- and 4-O-Allyl and -propargyl glucose and the corresponding oxime derivatives were prepared from readily available glucose dithioacetals. Intramolecular 1,3-dipolar cycloaddition of the N-benzyl and N-methyl nitrones of the above acyclic 2-O-allyl glucose derivatives led to the diastereoselective formation of chiral isoxazolidines incorporating the tetrahydrofuran ring. The EI mass spectra revealed a characteristic cleavage of the C-alkyl group adjacent to the furan oxygen atom. An enantiopure trisubstituted tetrahydrofuran was obtained by the reductive cleavage of the isoxazolidine ring of one of the cycloadducts. In contrast, the nitrile oxide cycloaddition of the 2-O-allyl derivatives afforded diastereomeric mixtures of the corresponding dihydroisoxazolines, the stereochemistry of which was tentatively assigned on the basis of the principle of optical superposition. The exclusive formation of a tetrahydrofuran ring from pentaallyl nitrone or nitrile oxide demonstrated the preferred formation of a five-membered ring to that of six or seven-membered rings. The nitrile oxide generated from a 3,4,5,6,7-pentaallyloxy-1-nitroheptane derivative obtained from pentaallylglucose underwent diastereoselective cycloaddition to give an isoxazoline fused to a pyran ring. Enantiopure isoxazoles containing tetrahydrofuran and oxepane rings were also prepared in good yields by the nitrile oxide cycloaddition of the 2-O- and 4-O-propargyl derivatives.     

A stereoselective method for the synthesis of enantiopure 3-substituted 4-hydroxyproline derivatives via 1,3-dipolar cycloadditions

The stereoselective 1,3-dipolar cycloaddition between (Z)-1,4-dichloro-2-butene and a menthone-derived nitrone led to the corresponding isoxazolidine. Regioselective azidation of a single chlorine atom followed by another Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) induced enantiopure 1,2,3-triazolyl-functionalized isoxazolidines. The subsequent acidic cleavage of the menthone chiral auxiliary and reductive cleavage of the isoxazolidine N–O bond triggered an intramolecular cyclization through the displacement of the second chlorine. This rapid and stereoselective synthetic strategy provided reliable access to a series of enantiopure 3-substituted 4-hydroxyproline derivatives.     

1,3-Dipolar cycloaddition approach to pyrrolidine analogues of C-nucleosides related to pseudouridine

Pyrrolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of uracil-5 and 2,4-dimethoxypyrimidine-5 nitrones with allyl alcohol and methyl acrylate, and subsequent reductive cleavage of the isoxazolidine cycloadducts. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the pyrrolidine ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed.     

Intramolecular 1,3-dipolar cycloaddition of N-alkenyl nitrones en route to glycosyl piperidines

Stereoselective intramolecular 1,3-dipolar cycloaddition of homochiral N-(alkenylglycosyl)nitrones, prepared by allylation of C-(glycosyl)nitrones and subsequent oxidation, is described. The previously described 2-aza-Cope rearrangement was not observed for these substrates, but evidences of E/Z isomerism during the cycloaddition were obtained. The obtained cycloadducts can serve as key precursors of imino disaccharide analogues. This is exemplified by a short route to a protected 2-furanosyl-4-hydroxy-6-phenyl piperidine.     

Synthesis of novel chiral bis(2-oxazolinyl)xanthene (xabox) ligands and their evaluation in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone

Chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) were synthesized and the chiral environments were evaluated in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones resulting in good to excellent enantioselectivities. 1,3-Dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone in the presence of a bis(2-oxazolinyl)xanthene (4c; xabox-Bn) and Mn(II) or Mg(II) complex as a chiral Lewis acid catalyst proceeded smoothly to give the corresponding cycloadducts ranging from 96:4 to >99:1 of endo:exo ratio and ranging from 91% to 98% ee for the endo adduct.     

Stereoselective synthesis of novel annulated thiopyrano indole derivatives from simple oxindole via intramolecular 1,3-dipolar cycloaddition reactions of nitrone and nitrile oxide

Synthesis of some novel isoxazolidine/dihydroisoxazole annulated thiopyrano[2,3-b]indole derivatives from simple oxindole via 1,3-dipolar cycloaddition reaction involving nitrone and nitrile oxide as 1,3-dipole is reported.     

Dipolar cycloaddition of N-aryl-C-(2,2-dichloro-1-phenylcyclopropyl)nitrones to N-arylmaleimides

1,3-Dipolar cycloaddition of N-aryl-C-(2,2-dichloro-1-phenylcyclopropyl)nitrones to N-arylmaleimides stereoselectively gives substituted pyrrolo[3,4-d]isoxazolidines as mixtures of two diastereoisomers differing by configuration at the C^1′ atom of the cyclopropane ring in the substituent on C³. Substituents in the aromatic rings of the initial nitrone and maleimide do not affect the stereochemistry of the process.