Gold‐Catalyzed Cycloaddition Reactions of Ethyl Diazoacetate,Nitrosoarenes, and Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and Benzo[b]azepine Derivatives

Gold‐catalyzed cycloadditions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl species to yield isoxazolidine derivatives stereoselectively are described. Treatment of these isoxazolidine products with the same catalyst results in a novel 1,2‐H shift/[3,3] rearrangement to give benzo[b]azepine compounds. The mechanism of this skeletal rearrangement is elucidated with deuterium‐labeling experiments.     

Evolution de quelques isoxazolidines en milieu basique

The reaction of sodium methylate with 2-phenyl-3-benzoyl (or 3-phenyl) isoxazolidine leads, depending on the substituents of the heterocycle, to enamines, hydroxy lactams, enol lactams resulting from cleavage or rearrangement of the isoxazolidine. Formation of enamines in the reaction mixture during the course of the cycloaddition between C-benzoyl N-phenyl nitrone and certain olefins is due to hydrogen abstraction at carbon 3 of the isoxazolidine ring by the nitrone.     

Enantioselective synthesis of cocaine C-1 analogues using sulfinimines (N-sulfinyl imines)

The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,β-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O(t)Bu)(3) the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.     

Copper‐Catalyzed Three‐Component Annulations of Alkenes,Nitrosoarenes, and N‐Hydroxyallylamines To Form Fused Oxazinane/Isoxazolidine Heterocycles

One‐pot cascade annulations among nitrosoarenes, alkenes, and N‐hydroxyallylamines have been achieved with CuCl/O₂ catalysts, forming fused oxazinane/isoxazolidine heterocycles with excellent diastereoselectivity (d.r. >20:1). To enhance the synthetic utility, we developed a successive cleavage of the two N−O bonds of the resulting heterocycles. A mechanism involving dipolar [3+2] cycloadditions of nitrone intermediates with their tethered alkenes is postulated for formation of these heterocycles.     

Copper‐Catalyzed Three‐Component Annulations of Alkenes,Nitrosoarenes, and N‐Hydroxyallylamines To Form Fused Oxazinane/Isoxazolidine Heterocycles

One‐pot cascade annulations among nitrosoarenes, alkenes, and N‐hydroxyallylamines have been achieved with CuCl/O₂ catalysts, forming fused oxazinane/isoxazolidine heterocycles with excellent diastereoselectivity (d.r. >20:1). To enhance the synthetic utility, we developed a successive cleavage of the two N−O bonds of the resulting heterocycles. A mechanism involving dipolar [3+2] cycloadditions of nitrone intermediates with their tethered alkenes is postulated for formation of these heterocycles.     

Intramolecular cycloadditions of alpha-allyloxycarbonylnitrones: stereoselective synthesis of 3-amino-2(5H)furanones

Treatment of furoisoxazolidines with NaH leads to functionalized 3-amino-2(5H)-furanones through a new rearrangement pattern of the isoxazolidine nucleus. This process has been usefully exploited for the synthesis of enantiomerically pure (5R)-3-alkylamino-5-methyl-2(5H)-furanones.     

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.     

Synthesis of iminomethano-dibenzo[a,e]cyclooctenes by transannular formation and cleavage of isoxazolidines

Regioselective formation of the 7-azabicyclo[4,2,2]decanone (4) was accomplished by reaction of hydroxylamine with the enone (10) and subsequent reduction of the isoxazolidine adduct (11); intramolecular nitrone cycloaddition of (19) gave a 2:1 mixture of the regioisomers (17) and (18) which were reduced to give the bridgehead methylated, -hydroxylated, [3,3,2] and [4,2,2] iminomethano compounds (5) and (6).     

Synthesis and Antibacterial Activity of New 2,5‐Diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones

The synthesis of some biologically interesting pyrrolo‐isoxazolidine derivatives has been accomplished by the 1,3‐dipolar cycloaddition reaction of substituted open chain conjugated azomethine N‐oxides 1 with substituted N‐aryl maleimides 2 leading to the formation of new stereoisomeric 2,5‐diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives 3 in excellent yields. These stereoisomers have been characterized as cis‐ 3A and trans‐ 3B on the basis of their ¹H‐NMR spectral measurements. The synthesized compounds have been screened for their antibacterial activities and have been found to be active against the bacteria Escherichia coli and Pseudomonas aeruginosa up to a significant extent.     

New functionalizations of oxanorbornenic systems via 1,3-dipolar : cycloadditions with c,n-diphenylnitrone

The regio- and stereoselectivity of the cycloaddition between C,N-diphenylnitrone and 2-endo-acetoxy-7-oxabicyclo[2.2.1] hept-5-ene-2-exo-carbonitrile has been studied. Subsequent fragmentation of the isoxazolidine ring with mCPBA followed by acidic hydrolysis yields highly functionalized oxanorbonenic hydroxyketones.     

Synthesis of polyhydroxylated 7-aminopyrrolizidines and 8-aminoindolizidines

The ammonolysis of a lactone moiety in tricyclic cycloadducts derived from non-racemic five-membered cyclic nitrone and 2(5H)-furanones furnishes an amido function, which after subsequent Hofmann rearrangement, leads to a protected amino group attached to the bicyclic isoxazolidine skeleton. A successive simple transformation, involving cleavage of N-O bond followed by intramolecular N-alkylation, provides an access to the polyhydroxylated 7-aminopyrrolizidines and 8-aminoindolizidines, potential glycosidases inhibitors.     

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.     

Enantioselective nitrone cycloadditions of alpha,beta-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-cerium(IV) triflate complexes

[Structure: see text] Enantioselective nitrone cycloadditions with beta-substituted alpha,beta-unsaturated 2-acyl imidazoles catalyzed by bis(oxazolinyl)pyridine-cerium(IV) triflate complexes 1 have been reported. The isoxazolidine products were efficiently transformed into densely functionalized beta'-hydroxy-beta-amino acid derivatives.     

The reaction of amines with phthalimide derivatives a convenient synthesis of isoxazolidine

The reaction of tert-butylamine, isoxazolidine and hydrazine with N-[(3-chloropropyl)oxy]phthalimide is investigated. A convenient synthesis of oxazolidine is described.     

Selective [5,5]‐Sigmatropic Rearrangement by Assembly of Aryl Sulfoxides with Allyl Nitriles

Aromatic [5,5]‐sigmatropic rearrangement is an appealing protocol for accessing 1,4‐substituted arenes. However, such a protocol has not been well utilized in organic synthesis because of the difficulties in the synthesis of the substrates, selectivity issues, and limited substrate scope. Described herein is a new [5,5]‐sigmatropic reaction utilizing readily available aryl sulfoxides and allyl nitriles. This reaction features mild reaction conditions, high chemo‐ and regioselectivity, excellent functional‐group compatibility, and broad substrate scope. Computational studies suggest that the success of the reaction can be attributed to the selective electrophilic assembly of the rearrangement precursors, in which a linear ‐C=C=N‐ linkage favors [5,5]‐sigmatropic rearrangement over the competitive [3,3]‐sigmatropic rearrangement.     

Synthesis and Evaluation of Novel Spiro[oxindole‐isoxazolidine] Derivatives as Potent Antioxidants

The antioxidant activity of isatin derivatives can be described with the presence of enolic hydroxyl group at the second position of the ring because of the keto‐enol tautomerism between NH and CO groups of indolone moiety. The reducing ability of the tested compounds was evaluated by their interaction with the stable free radical 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) at various concentrations. Novel spiro[oxindole‐isoxazolidine] derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i ) have been synthesized by 1,3‐dipolar cycloaddition reactions of variously substituted maleimides ( 1 ) with isatin ketonitrone ( 3 ) and tested for their in vitro antioxidant potency in the DPPH assay. All the synthesized compounds have been identified as potent in vitro antioxidants.     

Mass spectrometric studies of cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a, 2,3,4‐tetrahydro‐lH‐azirino[1,2‐a]1,5]benzodiazepines

The mass spectrometric behaviour of four cis‐ and trans‐1a,3‐disubstituted‐1,1‐dichloro‐4‐formyl‐1a,2,3,4‐tetrahydro‐1H‐azirino [1, 2‐a][1,5]benzodiazepines has been studied with the aid of mass‐analysed ion kinetic energy spectrometry and exact mass measurements under electron impact ionization. All compounds show a tendency to eliminate a chlorine atom from the aziridine ring, and then eliminate a neutral propene or styrene from the diazepine ring to yield azirino [1,2‐b][1,3] benzimidazole ions. These azirino [1,2‐a][1,5]‐benzodiazepimes can also eliminate HCl, or Cl plus HCl simultaneously to undergo a ring enlargement rearrangement to yield 1,6‐benzodiazocine ions, which further lose small molecular fragments, propyne or phenylacetylene, with rearrangement to give quinoxaline ions.     

Tandem Insertion–[1,3]‐Rearrangement: Highly Enantioselective Construction of α‐Aminoketones

An enantioselective synthesis of α‐aminoketone derivatives were readily available through a tandem insertion–[1,3] O‐to‐C rearrangement reaction. The rhodium salt and chiral N,N′‐dioxide‐indium(III) complex make up relay catalysis, which enables the O?H insertion of benzylic alcohols to N‐sulfonyl‐1,2,3‐triazoles, and asymmetric [1,3]‐rearrangement of amino enol ether intermediates, subsequently. Preliminary mechanistic studies suggested that the [1,3] O‐to‐C rearrangement step proceeded through an ion pair pathway.     

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.     

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

A new diastereoselective route to 2‐aminotetrahydrofurans has been developed from N,O‐dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond‐forming [3,3]‐sigmatropic rearrangement followed by a C?O bond‐forming cyclization. A copper‐catalyzed N‐alkenylation of an N‐Boc‐hydroxylamine with alkenyl iodides, and a base‐promoted addition of the resulting N‐hydroxyenamines to an electron‐deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base‐promoted ring‐opening and Mannich reaction has been discovered to covert 2‐aminotetrahydrofurans to cyclopentyl β‐aminoacid derivatives or cyclopentenones.