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.     

Synthesis of cyclic and acyclic beta-amino acids via chelation-controlled 1,3-dipolar cycloaddition

Isoxazolidines have been synthesized in diastereomeric excess up to 94% via a MgBr2-induced chelation-controlled 1,3-dipolar cycloaddition reaction with N-hydroxyphenylglycinol as a chiral auxiliary. The diastereomerically pure isoxazolidines were further transformed into cyclic and acyclic beta-amino acid derivatives.     

Peracid-induced ring opening of some hexahydro-2H-isoxazolo[2,3-a]pyridines to second-generation cyclic aldonitrones

A study of the stereo- and face selectivity of the cycloaddition reactions of several mono- and disubstituted alkenes with 4-hydroxymethyl-3,4,5,6-tetrahydropyridine 1-oxide has been carried out. The addition reactions have displayed a very high degree of face selectivity in the range 13-48:1. Use of dimethyl methylenemalonate as a protective group in nitrone cycloaddition reactions has been demonstrated. The invertomeric analysis revealed that the bicyclic cycloadducts remain predominantly as the cis-fused isomer, which leads to the formation of synthetically important second-generation cyclic aldonitrones via peracid oxidation. One interesting finding was that treatment of the cycloadducts with two equivalents of peracid afforded the cyclic N-hydroxy lactams, presumably via further oxidation of the aldonitrones. The piperidine ring has been elaborated by cycloaddition reaction of the second-generation nitrones with several alkenes, which in most cases gave the cycloadducts in a stereoselective manner.     

Formal and standard ruthenium-catalyzed [2 + 2 + 2] cycloaddition reaction of 1,6-diynes to alkenes: a mechanistic density functional study

"Formal" and standard Ru(II)-catalyzed [2 + 2 + 2] cycloaddition of 1,6-diynes 1 to alkenes gave bicyclic 1,3-cyclohexadienes in relatively good yields. The neutral Ru(II) catalyst was formed in situ by mixing equimolecular amounts of [Cp*Ru(CH3CN)3]PF6 and Et4NCl. Two isomeric bicyclic 1,3-cyclohexadienes 3 and 8 were obtained depending on the cyclic or acyclic nature of the alkene partner. Mechanistic studies on the Ru catalytic cycle revealed a clue for this difference: (a) when acyclic alkenes were used, linear coupling of 1,6-diynes with alkenes was observed giving 1,3,5-trienes 6 as the only initial reaction products, which after a thermal disrotatory 6e-pi electrocyclization led to the final 1,3-cyclohexadienes 3 as probed by NMR studies. This cascade process behaved as a formal Ru-catalyzed [2 + 2 + 2] cycloaddition. (b) With cyclic alkenes, the standard Ru-catalyzed [2 + 2 + 2] cycloaddition occurred, giving the bicyclic 1,3-cyclohexadienes 8 as reaction products. A complete catalytic cycle for the formal and standard Ru-catalyzed [2 + 2 + 2] cycloaddition of acetylene and cyclic and acyclic alkenes with the Cp*RuCl fragment has been proposed and discussed based on DFT/B3LYP calculations. The most likely mechanism for these processes would involve the formation of ruthenacycloheptadiene intermediates XXIII or XXVII depending on the alkene nature. From these complexes, two alternatives could be envisioned: (a) a reductive elimination in the case of cyclic alkenes 7 and (b) a beta-elimination followed by reductive elimination to give 1,3,5-hexatrienes 6 in the case of acyclic alkenes. Final 6e-pi electrocyclization of 6 gave 1,3-cyclohexadienes 3.     

N,O-heterocyclics13;-14conversion of isoxazolidines into α,β enones

Substituted isoxazolidines formed by 1,3-dipolar cycloaddition of nitrones to alkenes undergo ring-opening elimination to α,β-enones when treated with trimethyl phosphate. The reaction involves initial alkylation giving the isoxazolidinium intermediate which collapses to the α,β-enone by a Hofmann-like elimination having an orientation controlled by electronic factors, the first step being rate-determining.     

Stereochemistry of substituted isoxazolidines derived from N-methyl C-diethoxyphosphorylated nitrone

Cycloadditions of N-methyl-C-(diethoxyphosphoryl)nitrone 1a to cyclic alkenes proceeded regio- and diastereospecifically. Reactions of 1a with 1,1-disubstituted alkenes led to the regiospecific formation of 5,5-disubstituted isoxazolidines 7/8 in nearly equimolar ratios, whereas additions to trans-1,2-disubstituted alkenes gave four isomeric isoxazolidines with up to 80% regioselectivity and moderate (up to 60%) diastereoselectivity. Stereochemistry of the substituted isoxazolidines was established based on the conformational analysis using vicinal H–H, H–P and P–C couplings, and was, in some cases, supported by geminal H–C–PO coupling and deshielding PO and CO effects.     

Asymmetric nitrone cycloadditions and their application to the synthesis of enantiopure pyrrolidine and pyrrolizidine derivatives

The cycloaddition reactions of a pair of chiral pyrroline-N-oxides derived from d-ribose with some typical mono and disubstituted alkenes are reported. In all these reactions with monosubstituted alkenes as well as with dimethyl maleate the preferred stereochemical outcome of the cycloaddition step comes from a 5-exo-anti transition state whereas stereoisomers from the 5-exo-syn transition state are also present as minor adducts. In the reaction with dimethyl fumarate the major adduct comes from a 4-exo-5-endo-syn transition state. The further behavior of the obtained isoxazolidines upon reductive ring opening conditions depends on the kind and the geometry of the preexisting substituents and they are transformed to enantiomerically pure pyrrolidine or pyrrolizidinone derivatives.     

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.     

Direct alkenylation of non-aromatic enamides via palladium-catalyzed oxidative coupling: Synthetic developments and applications

Direct C(3) alkenylation of non-aromatic enamides through palladium(II)-catalyzed Fujiwara–Moritani cross-coupling was developed. The reaction scope includes a range of cyclic enamides as well as activated alkenes. The utility of this methodology is illustrated by the synthesis of octa- or tetrahydroquinoline cores obtained from conjugated enamides via Diels–Alder cycloaddition.     

Catalytic enantioselective 1,3-dipolar cycloaddition reactions of cyclic nitrones: a simple approach for the formation of optically active isoquinoline derivatives

The first highly diastereo- and enantioselective catalytic 1, 3-dipolar cycloaddition reaction of cyclic nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. The nitrones, mainly 3,4-dihydroisoquinoline N-oxides, are activated by chiral 3,3'-aryl BINOL-AlMe complexes and undergo a regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction with especially alkyl vinyl ethers, giving the exo diastereomer of the cycloaddition products in high yield, >90% de and up to 85% ee. The reaction has been investigated under various conditions, and it is demonstrated that the reaction is an attractive synthetic procedure for the introduction of a chiral center in the 1-position of the isoquinoline skeleton. The mechanism of the reaction is discussed on the basis of the assignment of the absolute configuration of the cycloaddition product and theoretical calculations.     

Chiral hetero- and carbocyclic compounds from the asymmetric hydrogenation of cyclic alkenes

Several types of chiral hetero- and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P-Ligated iridium catalysts reduced six-membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five-membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five- rather than the six-membered cyclic alkenes. The major enantiomer formed in the reduction of six-membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3-cis-cyclohexane carboxylates.     

Stereoselektivität und Reaktivität bei der 1,3-dipolaren Cycloaddition chiraler N-(Alkoxyalkyl)nitrone

Stereoselectivity and Reactivity in the 1,3-Dipolar Cycloaddition of Chiral N-(Alkoxyalkyl)nitrones The stereoselectivity in the reaction of hydroxy-oxime 1 with acetaldehyde and methyl methacrylate yielding the diastereomeric isoxazolidine-ribosides 9–12 was determined to be 93%. The predominant adducts 9 and 10 were cleaved to the diastereomeric isoxazolidines 19 and 20 , respectively, which upon oxidation gave the same optically active 2-isoxazoline 21 , thus demonstrating the participation in the cycloaddition of both (E/Z)-isomeric nitrones 13 and 14 . Based upon comparison of the optical rotations, the isoxazolidines 7 , 8 , 19 and 20 and the 2-isoxazolines 21 and 22 possess the same chirality, found to be R by correlating 7 with (+)-(S)-citramalic acid. - Since the hydroxy-oximes 1 and 36 showed the same stereo-selectivity in the reaction with formaldehyde and methyl methacrylate, the trityl group of 1 does not influence the stereoselectivity in the cycloaddition. The hydroxyoxime 38 led in the same type of reaction to the isoxazolidines 7 , 8 , 19 and 20 possessing (S)-chirality, the stereoselectivity (79–95%) being similar to the one observed with 1 (67–95%). The explanation of this stereoselectivity is based upon a stereoelectronic effect in the transition state of the cycloadditions (kinetic anomeric effect). As predicted, the N-(alkoxyalkyl)nitrones showed enhanced reactivity in the cycloaddition with unactivated olefins (leading to 47 , 48 , 50 and 51 ). The importance of exo vs. endo approach of the dipolarophile was evidenced by reacting 1 with formaldehyde and methyl acrylate giving predominantly 57 with (5S)-configuration. - Use of the hydroxy-oxime 65 allows synthesis of optically active isoxazolidines with regeneration of the starting hydroxy-oxime.     

Versatile Spirocyclic Glycine‐Based Nitrones and Their Highly Stereoselective 1,3‐Dipolar Cycloaddition

A convenient and efficient method for the synthesis of novel spirocyclic nitrones prepared from glycine derivatives is reported. The 1,3‐cycloaddition reactions of the nitrones with alkenes lead to novel isoxazolidines in high yields and with excellent regio‐ and stereoselectivity.     

"N-acyliminium ion pool" as a heterodiene in [4 + 2] cycloaddition reaction

[reaction: see text] An N-acyliminium ion pool was found to undergo cycloaddition reaction with a variety of dienophiles such as alkenes and alkynes. A concerted mechanism seems to be most likely for alkyl-substituted alkenes as suggested by the DFT calculations, whereas a stepwise mechanism plays the major role for aryl-substituted alkenes. It is also noteworthy that the present study demonstrates the potential of the combination of the cation pool method and the micromixing in both mechanistic and synthetic aspects.     

SYNTHESIS,CHARACTERIZATION, AND BIOLOGICAL STUDIES OF NOVEL ISOXAZOLIDINES: 1,3-DIPOLAR CYCLOADDITION REACTIONS

ABSTRACT

1,3-Dipolar cycloaddition reaction of nitrones to olefins is of synthetic interest. In the present work, isoxazolidines have been synthesized in high yield via intermolecular cycloaddition of N-arylnitrone with monosubstituted olefins and are employed for biological evaluation.     

Carbocyclische Verbindungen aus Monosacchariden. II. Umsetzungen in der Mannosereihe

Carbocyclic compounds from monosaccharides. II. Transformations in the mannose series Upon treatment with Zn in refluxing aqeous ethanol or butanol, the anomeric mannopyranosides 11 and 14 yielded the aldehyde 15 which was subjected (via its N-methyl-nitrone) to an intramolecular nitrone-olefine cycloaddition leading diastereoselectively to 18 in a yield of 64% from 14 . Minor products of this reaction sequence were the compounds 19 , 20 and 21 . Similarily, the easily accessible unsaturated furanose 26 , upon treatment with N-methyl-hydroxylamine gave the isoxazolidines 27 (84%) and 28 (3%), thus showing that a free 4-hydroxy group is not detrimental to this intramolecular nitrone-olefin cycloaddition. The configuration of 18 , 27 and 28 (resp. 29 ) were determined by spectroscopic means; that of 27 was further proven by transformation into the compound 31 , of which an X-ray analysis was performed.     

1,3-dipolar cycloaddition on solid supports: nitrone approach towards isoxazolidines and isoxazolines and subsequent transformations

1,3-dipolar cycloaddition reactions of nitrones with alkenes and alkynes are well-studied reactions in solution-phase organic chemistry. However, the number of studies concerned with their application in solid-phase organic synthesis is rather low compared to other 1,3-dipoles, e.g. azides or nitrile oxides. This tutorial review aims to summarise the main approaches towards the application of nitrones in 1,3-dipolar cycloaddition reactions on solid supports in addition to subsequent transformations with polymer-bound isoxazolidines and reactions using polymer-bound catalysts.     

Catalyst‐Free Regioselective [3+2] Cycloadditions of α,β‐unsaturated N‐arylnitrones with Alkenes to Access Functionalized Isoxazolidines: A DFT Study

The catalyst‐free regioselective [3+2]‐cycloaddition of α,β‐unsaturated N‐arylnitrones with alkenes are developed. The series of synthetically important functionalized isoxazolidines are prepared in good to excellent yields by step economic pathway under ligand and transition‐metal‐free conditions. The regioselective cycloaddition pathway supported by control experiment and computational study.     

Chiral Hetero‐ and Carbocyclic Compounds from the Asymmetric Hydrogenation of Cyclic Alkenes

Several types of chiral hetero‐ and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P‐Ligated iridium catalysts reduced six‐membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five‐membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five‐ rather than the six‐membered cyclic alkenes. The major enantiomer formed in the reduction of six‐membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3‐cis‐cyclohexane carboxylates.     

New approach for the synthesis of isoxazoline-N-oxides

A strategy for the synthesis of isoxazoline-N-oxides (cyclic five-membered nitronates) from primary nitro compounds and olefins is described. The key step of the process involves 1,3-dipolar cycloaddition of corresponding 1-bromosilyl nitronates with alkenes. [reaction: see text]