Diastereoselective synthesis of pyrrolidines via 1,3-dipolar cycloaddition of a chiral azomethine ylide

1,3-Dipolar cycloaddition of d-glucose-derived azomethine ylides for the synthesis of chiral pyrrolidines accompanied an unexpected 1,2-elimination in the furanose moiety of the products. The C3′ alkoxy/hydroxy group of the furanose moiety was invariably eliminated under the reaction conditions. Also, in contrast to the previous reports, moderate to good exo-diastereoselectivity was observed in the reaction products.     

Three-component couplings for the synthesis of pyrroloquinoxalinones by azomethine ylide 1,3-dipolar cycloaddition chemistry

1-Methyl-3,4-dihydroquinoxalin-2(1H)-one was heated with a range of aldehydes to generate intermediate azomethine ylides which underwent [3 + 2] cycloaddition reactions with N-methyl or N-phenylmaleimide to give substituted tetrahydropyrroloquinoxalinones. Only one (racemic) stereoisomer was formed in each case and the stereochemical outcome was verified by single crystal X-ray analysis. The products from this multicomponent reaction could be oxidised with DDQ to the pyrroloquinoxalinones.     

The stereoselective synthesis of novel macrolide antibacterial agents via an intramolecular 1,3-dipolar cycloaddition of azomethine ylide

An intramolecular 1,3-dipolar cycloaddition of azomethine ylide, generated in situ via the reaction of C12-glycinate derivative of macrolide with formaldehyde, provided a novel tricyclic macrolide. The high stereoselectivity of this [2+3] reaction was achieved by introducing a suitable directing group at C-6 position of macrolide.     

Stereocontrolled synthesis of triazacyclopenta[cd]pentalenes by intramolecular 1,3-dipolar cycloaddition reactions of azomethine imines

The construction of triazacyclopenta[cd]pentalene diesters 6 by the reaction of dihydropyrrole alpha-ketoesters 3 with acylated hydrazines was evaluated further as a potential central strategic step in the total syntheses of complex guanidine alkaloids such as palau'amine and styloguanidine. Successful cyclocondensations were realized with acid-stable 2,2,2-trichloroethyl carbazate and thiosemicarbazide, but not tert-butyl carbazate. The substituent on the pyrrolidine nitrogen can be alkoxycarbonyl, sulfonyl, or an N-alkyl-2-acylpyrrole group. Siloxy substitution at C1 of the alpha-ketoester side chain is also tolerated.     

Microwave-assisted facile synthesis of [a]-annelated pyrazolopyrroloindoles via intramolecular azomethine imine 1,3-dipolar cycloaddition

The synthesis of [a]-annelated pyrazolopyrroloindoles via intramolecular 1,3-dipolar cycloaddition of in situ generated azomethine imine from N-allylated indole-2-carboxaldehyde, in regio- and stereoselective manner by using microwave irradiation is described. A one-pot strategy for the expedient synthesis of pyrazolopyrroloindoles has been developed.     

Total synthesis of tropinone using 1,3-dipolar cycloaddition of cyclic azomethine ylide and phenyl vinyl sulfone as the key step

Total synthesis of tropinone from the readily available piperidone 2 is described. The rapid assembly of the tropane skeleton was achieved by 1,3-dipolar cycloaddition of cyclic azomethine ylide 3 to phenyl vinyl sulfone.     

Synthesis of spiropyrrolidinyl-benzoisothiazoline derivatives by 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide

The new spirocyclic compounds, spiropyrrolidinyl-benzoisothiazoline derivatives were synthesized by the 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide. The stereochemistry of 1,3-dipolar cycloaddition as well as the stereochemistry of Knoevenagel condensation of benzoisothiazole-2,2-dioxide with aldehydes were studied.     

A versatile cascade of intramolecular Vilsmeier-Haack and azomethine ylide 1,3-dipolar cycloaddition toward tricyclic cores of alkaloids

In the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a cascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition. Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to excellent yields.     

Chemoselective 1,3-dipolar cycloadditions of azomethine ylide with conjugated dienes

Methods are described of synthesizing various 3-carboxy-4-vinyl pyrrolidines, versatile building blocks for our drug discovery efforts. The 1,3-dipolar cycloaddition between activated olefins and nonstabilized azomethine ylide is a known method for synthesizing pyrrolidines in a stereospecific manner. Steric and electronic effects on the chemoselectivity of the 1,3-dipolar cycloaddition between azomethine ylide and α,β,γ,δ-unsaturated carboxylates have been explored.     

1,3-dipolar cycloaddition reactions of porphyrins with azomethine ylides

[reaction: see text] The behavior of porphyrins as dipolarophiles in 1,3-dipolar cycloadditions with azomethine ylides was studied. Depending on the nature of the substituent groups on the porphyrin macrocycles, the reaction can give monoadducts (chlorins) or bisadducts (isobacteriochlorins and bacteriochlorins). When a large excess of azomethine ylide is used, trisadducts can also be obtained. Mixed isobacteriochlorin derivatives were prepared from the reaction of azomethine ylides with the chlorin monoadducts previously obtained via Diels-Alder reactions.     

Asymmetric synthesis of spirocyclohexanone-pyrrolidine via AgI-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Cinchonine was effectively used in an AgOAc-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 2,6-bis(arylmethylidene) cyclohexanones, affording spiropyrrolidine derivatives with excellent yields (up to 99%), diastereoselectivities (up to 96:04 dr), and enantioselectivities (up to 99% ee).     

Stereoselective synthesis of functionalized pyrrolidines by ruthenium porphyrin-catalyzed decomposition of alpha-diazo esters and cascade azomethine ylide formation/1,3-dipolar cycloaddition reactions

[reaction: see text] Ruthenium porphyrins catalyze three-component coupling reaction of alpha-diazo esters with a series of N-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium-carbene intermediate and its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.     

Stereospecific route to 5,11-methanomorphanthridine alkaloids via intramolecular 1,3-dipolar cycloaddition of nonstabilized azomethine ylide: formal total synthesis of (+/-)-pancracine

The core structure of the complex pentacyclic 5,11-methanomorphanthridine alkaloids is constructed stereospecifically in one step employing an intramolecular [3 + 2]-cycloaddition of nonstabilized azomethine ylide as the key step. The strategy is demonstrated by accomplishing the formal total synthesis of (+/-)-pancracine. [reaction: see text]     

Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines

The reaction of alkene-tethered alpha-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. alpha-Methoxy-alpha,beta-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. alpha-Ketoesters, alpha-ketoamides, and alpha-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.     

Highly enantioselective asymmetric 1,3-dipolar cycloaddition of azomethine ylide catalyzed by a copper(I)/ClickFerrophos complex

A copper(I)/ClickFerrophos complex catalyzed the asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with vinyl sulfone to give the exo-2,4,5-trisubstituted pyrrolidine in good yield with high enantioselectivity (99% ee). The complex also effectively catalyzed reactions of other dipolarophiles such as acrylates, maleate, and maleimides to give the exo-2,4,5-, and 2,3,4,5-substituted pyrrolidine derivatives with high diastereo- and enantioselectivities.     

Asymmetic organocatalytic 1,3-dipolar cycloaddition of azomethine ylide to methyl 2-(2-nitrophenyl)acrylate for the synthesis of diastereoisomers of spirotryprostatin A

The total synthesis of two diastereomers of spirotryprostatin A has been established starting with an asymmetric 1,3-dipolar cycloaddition of methyl 2-(2-nitrophenyl)acrylate with azomethine ylides catalyzed by a Br?nsted acid.     

The catalytic asymmetric 1,3-dipolar cycloaddition of ynones with azomethine ylides

The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbon-carbon triple bonds with azomethine ylides has been established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in perfect enantioselectivities of up to >99% ee.     

Catalytic enantioselective 1,3-dipolar cycloaddition of azomethine ylides with vinyl sulfones

[reaction: see text] A general protocol for the enantioselective catalytic 1,3-dipolar cycloaddition of azomethine ylides with aryl vinyl sulfones is described. Nearly complete exo selectivity and enantioselectivities up to 85% ee are attained with Cu(CH(3)CN)(4)ClO(4)/Taniaphos as the catalyst system. The resulting enantioenriched 3-sulfonyl cycloadducts are versatile intermediates in the synthesis of 2,5-disubstituted pyrrolidines.     

Ultrasound-promoted regioselective and stereoselective synthesis of novel spiroindanedionepyrrolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

A series of novel spiroindanedionepyrrolizidines have been synthesized by multicomponent 1,3-dipolar cycloaddition of a variety of (E)-3-aryl-1-(thiophen-2-yl)prop-2-en-1-ones with unstabilized azomethine ylides generated from ninhydrin and l-proline. The reactions were highly regioselective and stereoselective and were conducted with both conventional heating and ultrasonic irradiation conditions. In general, milder conditions, and moderate improvement in rates, reaction times, and yields were observed when the reactions were performed under ultrasonic conditions. The regioselective and stereoselective nature of the products was established by use of single-crystal X-ray structure and spectroscopic techniques.