1 , 3-Dipolar cycloadditions of mesitonitrile oxide to chiral α , β-unsaturated enones catalyzed by Lewis acids

The influence of MgBr2, MgI2 and Ti(OiPr)4 on the regioand stereoselective outcome of 1,3dipolar cycloaddition of mesitonitriloxide 1 to both E and Z isomers of (5S)-5,6-(Oisopropylidenedioxa)hex-3-en-2-one (2a) or (4S)-1-(2-furyl)-4,5-(O isopropylidenedioxa) pent3-en-1-one (2b) was studied. Addition of Lewis acids in some cases has a dramatic effect on the regiochemistry as well as on the diastereomeric ratio of cycloadducts.


Introduction
The development of 1,3-dipolar cycloaddition reactions has in recent years entered a new stage as control of the stereochemistry in the addition step became the major challenge.The stereochemistry of 1,3-dipolar cycloaddition reactions can be controlled by either choosing the appropriate substrates or controlling the reaction by a metal complex acting as a catalyst.][3][4][5] An impressive effort has been devoted to the synthetic application of 1,3-dipolar cycloaddition of nitrile oxides. 6,77][8] Thus, from E alkenes 4,5-anti products are obtained, while Z alkenes afford 4,5-syn compounds.A large part of the research in this area dealt with the influence exerted by stereocentre located in either one of the two cycloaddends, with the stereochemical outcome of the reaction.The low degree of stereoselection generally showed by the cycloaddition of chiral nitrile oxides promoted an intense research activity on the use of chiral alkenes as dipolarophiles.The basic factors governing the stereochemical course of these reactions are summarized in research work of R. Annunziata and coworkers. 9he regioselectivity phenomena are a case of competition between two different modes of union of unsymetrical reactants, hence the electronic and steric effects on reactivity have to be confronted.The nitrile oxides cycloadditions to terminal alkenes proceed rapidly and with complete regioselectivity to yield only 5-substituted isoxazolines as unique products. 6On the other hand, reactions of nitrile oxides with 1,2-disubstituted internal alkenes are sluggish and mostly mixture of regioisomeric isoxazolines are formed. 7,8The use of alkenes with chiral center arises as well the problem of diastereoselectivity, which is generally not very high and depends mainly upon the nature of both the dipole as well as the dipolarophile.When 1,3-dipolar cycloaddition is to be used in any synthesis of a complex target molecule, a method that accomodates change or even reversal of the regio-or diastereoselectivity would be desirable.Recently, 1,3-dipolar cycloadditions of chiral α,β-unsaturated enones of glyceraldehyde type with azomethine ylides, 10,11 diazo-compounds, 12 nitronates 13 and nitrilimines 14 were described.Based on this facts we decided to investigate stereochemical behavior the cycloadditions of mesitonitrile oxide ( 1) with E and Z isomers of enones (5S)-5,6-(O-isopropylidenedioxa)hex-3en-2-one (2a) and (4S)-1-(2-furyl)-4,5-(O-isopropylidenedioxa)pent-3-en-1-one (2b), as well as the influence of some Lewis acids (MgBr 2 , MgI 2 , Ti(OiPr) 4 ) on regio-and stereochemical outcome of these 1,3-dipolar cycloadditions.

Results and Discussion
The mesitonitrile oxide (1) was chosen for afore mentioned cycloadditions as one of the most stable nitrile oxide with minimum side reactions and the enones Z-2a , E-2a 15a,b and Z-2b, E-2b (firstly prepared by us) as electron deficient dipolarophiles.7][18] As a starting material was used (R)-2,3-(O-isopropylidene) glyceraldehyde (3) prepared from commercially available 1,2:5,6-di(O-isopropylidene)-D-manitol by oxidative cleavage with sodium metaperiodate. 19As we would like to obtain both isomers (E and Z) the Wittig reaction was realized in polar solvent (methanol) and at the lower temperature (from 0 to -15°C).The enones E-2a and Z-2a were obtained in the ratio 60:40 in two steps with overall yield 58%.The enones E-2b and Z-2b were prepared in four steps starting from 2-(bromoacetyl)furane 20 via particular phosphonium bromide to the corresponding ylide, which by Wittig reaction with chiral (R)-2,3-(O-isopropylidene)glyceraldehyde afforded enones 2b, as a mixture of E and Z isomers (65 : 35) in overall yield 42%.The pure E and Z isomers were isolated by chromatography on silica gel using isohexane/ethyl acetate (5:1) as eluent.
The 1,3-dipolar cycloaddition reactions were firstly carried in absence of any catalyst, afterwards MgBr 2 , MgI 2 or Ti(OiPr) 4 were used as catalyst.Change of solvent or alteration of reaction temperature had only slight influence on the regio-and diastereoselectivity of the reaction.The results and reaction conditions of all experiments are summarized in Table 1.Ratio of regioisomers, as well as the relative configuration of the substituted isoxazolines (Scheme 1) were elucidated by various NMR methods.The ratio of regioisomers have been determined by integration of regioisomeric adducts in the 1 H NMR spectra of crude reaction mixtures and corresponds closely to those obtained by the chromatographic separations.All noncatalyzed cycloadditions of mesitonitrile oxide and enones E-2a, Z-2a and E-2b gave the mixture of both regioisomers with prevailing cycloadduct 4-acyl substituted isoxazolines, characterized by C-5/C-6 anti relationship (Table 1, entries 1, 5, 6, 16, 17).The enone Z-2b gave as a main products the second possible regioisomer (5-acylsubstituted isoxazolines) with totally opposite C-4/C-6 syn configuration (entries 11 and 12).In the cycloadditions of enones E-2a, Z-2a and 2b under catalysis no or only a slight change of regio-and diastereoselectivity was observed (entries 2, 7, 8, 18).In accordance with obtained experimental results we suppose that both, catalyzed and noncatalyzed cycloadditions of afore mentioned enones could be characterized by the similar transition states (Scheme 2, model B and chelated model).In the case of Z isomers chelated 7-membered metalocycle can be formed through the chelatation of Mg 2+ ion and two oxygen atoms and this transition state corresponds to the model B (Scheme 2), where the selectivity of the cycloaddition is determined by the influence of the "inside alkoxy" effect (Scheme 2, attack 1).Therefore predominantly 4-acyl C-5/C-6 anti isoxazolines 4a and 4b are formed (Table1, entries 2,7,8).The use of MgI2 most probably inhibited the cycloaddition of enones Z-2a and E-2a, so only the traces of the cycloadducts could be identified ( Table 1, entry 3, Table 2, entry 5).In the case of enone Z-2a 4-acyl-3,5-disubstituted isoxazole 12 was isolated from reaction mixture in 13% yield, the rest of reaction mixture was the non-identified tars.c Only traces of cycloadduct were detected in crude reaction mixture.

Scheme 2
More interesting results were obtained in cycloadditions of both enones E-2b and Z-2b to mesitonitrile oxide (1) under catalysis with magnesium halogenides.Apart from stereochemical outcome the cycloaddition of E-2b in the presence of MgBr 2 where only very slight growth of cycloaduct 8b was observed (Table 2, entry 9), in other cases both magnesium halogenides significantly improved regio-and diastereoselectivity.In the case of enone Z-2b, total reversal of regiochemistry occured, together with the change of diastereoselectivity (Table 1, entries 7, 8) and 4-furoylsubstituted isoxazolines 4b and 5b were formed as a main product with preponderance of C-5/C-6 anti relationship.The same dramatic improvement of regio-and stereoselectivity has been observed in cycloaddition reactions of enone E-2b under catalysis with MgI 2 -I 2 (Table 2, entry10).The complete reversal of regiochemistry of Z-2b in cycloadditions can be rationalized by different transition state of noncatalyzed and catalyzed cycloaddition (with different geometry).The electronic repulsion between nitrile oxide oxygen and oxygen atom of the alkoxy group, together with the bulky 2-furoyl group inhibits the cycloaddition through the Model B (Scheme 3, attack 4) and so predominantly 5-furoyl C-4/C-6 syn and 5-furoyl C-4/C-6 anti isoxazolines 7b and 6b are formed through Model A (Scheme 3, attack 5).The chelatation of Z-2b with Mg 2+ ions prefer the cycloaddition through the Model B (Scheme 2, chelated model, R= 2-furoyl) generating 4-furoylsubstituted 5/6 anti isoxazolines (Table 1, entries 7, 8).
The products of cycloadditions were isolated by flash column chromatography on silica gel and the pure diastereomers are characterized by characteristic physical constants and via analysis their 1 H NMR and 13 C NMR spectral data.The ratio of isomers was determined from 1 H NMR spectra, by integration of the peaks from H-4 a H-5 protons of isoxazolines.The structures and stereochemistries of prepared cycloadducts were eluciated on the base of 1 H and 13 C NMR spectra, using the selective decapling, heterocorelated 2D spectra and n.O.e difference experiments.All 1 H NMR characteristics of proton H-4, H-5 and H-6 are summarized in the Table 3.The chemical shifts and spin multiplicity of protons H-4 and H-5 of isoxazoline ring obtained from 1 H NMR spectra were the decisive informations for the structural assigments of both regioisomers (4-acyl or 5-acyl).The stereochemistry of the cycloadducts was identifioed by spectroscopic analysis, particularly by n.O.e.difference experiments.
In conclusion, use of MgX 2 halogenides in 1,3-dipolar cycloadditions of mesitonitrile oxide to chiral α,β-unsaturated enones (using both E and Z isomers) improved the regio-and stereoselective outcome of those reactions.Predominantly 4-acylsubstituted C-5/C-6 anti isoxazolines were formed.In one case (enone Z-2b) the addition of catalyst caused the total reversal of regiochemistry and stereochemistry.

Experimental Part
General Procedures.All melting points were determined with a Kofler hot-stage apparatus, the IR spectra were taken with-Philips analytical PU 9800 FTIR spectrometer in KBr pellets, the 1 H and 13 C NMR spectra were recorded on Varian VXR-300 and Varian Gemini 2000 spectrometer ( 1 H 300 MHz, 13 C 75 MHz) in deuterochloroform solutions.Chemical shifts are expressed in ppm from internal standard (tetramethylsilane, δ) and coupling constants are in hertz (Hz).TLC analyses were carried out with UV 254 silica gel plates (Merck).Flash chromatography was done on silica gel 60 (0.040-0.063 mm, Merck).Optical rotations [α] D were measured on IBZ Messtechnik Polar-LµP polarimeter at the sodium D line (589 nm) using a 1 dm cell at 25 °C in methanol.Elemental analyses were caried out on Carlo Erba CHNS-O 1108 apparatus and their results were found to be in good agreement with calculated values.Mesitonitrile oxide (1) was prepared according to literature. 21Reagents MgBr 2 and MgI 2 were freshly prepared prior to use, tetraisopropoxytitane is comercially available (Merck).(R)-2,3-(O-Isopropylidene)glyceraldehyde was prepared from 1,2:5,6-di(O-isopropylidene)-Dmanitol by oxidative cleavage with NaIO 4 . 19Starting enones (S)-5,6-(O-isopropylidene)hex-3ene-2-one (Z-2a and E-2a) were prepared similarly to literature 15b (using different solvent and reaction temperature).The yields in experimental part are given for isolated cycloadducts after column chromatography.The ratio of regio-and diastereomers was determined from NMR spectra of crude reaction mixtures.
The reaction was quenched with saturated NH 4 Cl water solution and extracted with diethylether (10 ml).Combined organic layers were dried over Na 2 SO 4 and the solvent was removed by rotary evaporation.

1,3-Dipolar cycloadditions of mesitonitrile oxide (1) with the enone 2. General procedure, without catalyst
Mesitonitrile oxide (1, 1 mmol) and corresponding enone (1 mmol) dissolved in 10 ml of dry solvent (the appropriate solvent, reaction time and temperature are listed in Table1 and Table 2) were stirred under reflux until complete conversion of nitrile oxide 1 (monitored by TLC).The solvent was evaporated under vacuum and the products were isolated by flash column chromatography on silica (hexanes/ethyl acetate).

with MgBr 2 or MgI 2 as catalyst.
The reactions were carried out under argon atmosphere.To the stirred solution of MgBr 2 or MgI 2 (1 mmol) in dry solvent (6 ml), was added the solution of mesitonitrile oxide (1, 1 mmol) in dry solvent (2 ml) by portions and the mixture was stirred 15 min at room temperature.The solution of corresponding enone (1 mmol) in dry solvent (2 ml) was added dropwise and reaction mixture was stirred under reflux (monitored by TLC).The solvent was removed under vacuum and if MgBr 2 was used as catalyst, the residue was diluted with CH 2 Cl 2 (10 ml), the solid was filtered off and solvent removed by rotary evaporation; in the case of MgI 2 , the residue was diluted with CH 2 Cl 2 (10 ml), washed twice with 10% solution of Na 2 S 2 O 3 to remove I 2 , dried over Na 2 SO 4 and the solvent was removed under vacuum.The products were isolated by flash column chromatography on silica (hexanes/ethyl acetate).