Synthesis of new optically pure isoxazolines via 1,3-dipolar cycloaddition of nitrile oxides with allyl esters derived from eugenol

1,3-dipolar cycloaddition of arylnitrile oxides with allyl ester prepared from eugenol afforded new chiral isoxazolines in good yields. The chemical structure of this compounds was characterized by 1 H NMR, 13 C NMR, 2D NMR and TOF-MS analysis. All the cycloadducts were obtained through a regiospecific and stereospecific pathway and all cases, only one isomer was isolated, as established by unambiguous NMR analysis.


INTRODUCTION
Heterocyclic; compounds have a wide range of applications in synthetic organic chemistry. Especially, isoxazolines: are of considerable interest due to their versatile applications in pharmaceutical and agrochemical fields. Isoxazoline derivatives: have been reported to possess anti influenza virus, [1] glycoprotein IIb/IIIa receptor antagonists, [2] antidiabetic, [3] antitumour, [4] antifungal, [5] analgesic, anti-inflammatory, [6] spermicidal and anti HIV, [7] β-adrenergic receptor antagonist, [8] antistress [9] and anticancer properties. [10] In fact, the combrestatine A-4, analogous 1-3 and the Avicine 4 compound derived from isoxazolines possess anti-cancer activities. [11] Anti-cancer analogues of theCombrestatine A-4 The 1,3-dipolar cycloaddition reactions represent: one of the best method, for the preparation of five-membered heterocycles, [12] and natural products. [13] In particular, the 1,3-dipolar cycloaddition: of nitrile oxides with alkenes and alkynes afforded isoxazolines, which are used as intermediates for the synthesis of-amino alcohols and alkaloids. [14,15] In order,, to increase, the activities of the cycloadducts, we have used the eugenol [4-allyl-2methoxyphenol] as a precursseur of the dipolarophiles: because it is well known that ,this natural compound, have different biological activities: such as antispasmodic, [16] antipyretic, [17] anti-inflammatory, [18] and antibacterial activities. [19] Herein, we report :an efficient and practical procedure for the preparation of new optically pure isoxazolines 7(ad-cf) via the 1,3-dipolar cycloaddition of the arylnitrile oxides with esters, synthesized from eugenol and having a terminal double bond. The reaction was carried out in toluene at 80 ° C without a catalyst.

1(a-c)
Scheme 1-Synthesis of the optically pure esters derived from eugenol and amino acid.
Arylnitrile oxides were easily generated in situ from benzohydroxyaminoyl chlorides 6(d-f) with triethylamine in toluene according to a known procedure. [21] The cycloaddition reaction of dipolarophiles 5(a-c) with the arylnitrile oxides at reflux of toluene for 48h (Scheme2) afforded the isoxazolines 7(ad-cf) with good yields as indicated in table 1.

Regiochemistry and stereochemistry of the cycloaddition
Two possible regioisomers: I and II, can be theoretically formed (Scheme 3) [22]. In practice, we have obtained: only one product as evidenced by TLC and 1 H NMR examination of the crude mixture. Cycloadducts 7(ad-cf) have been purified by a column chromatography, and characterized by NMR ( 1 H and 13 C). Based on the literature, [23] and the 13 C NMR, we can conclude: that the new cycloadducts possess: the same stereochemistry as detailed below. The cycloaddition of the amino esters 7(ad-cf) with the arylnitrile oxides: led to new cycloadducts, having a new chiral center: the quaternary carbon, linked to the substituted phenyl, group of the isoxazoline ring.  showed signals at C 80.9 and 155.9 atributable to the bearing oxygen carbon C5 and C3 of imine fonction, respectively. In addition, a whole set of linkages confirming the molecular structure of compound 7cd was reinforced by the HMBC spectrum which showed correlations: between the proton H4 and C1', C3 , C5 and C6 as well as correlations, between H2',6' and C1', C3 and C4'. Moreover, the regiochemistry was confirmed by the NOE, observed: between the protons H4 and the aromatic protons H2',6'. Although, in this study, the novel isoxazoline derivatives 7(ad-cf) were formed as an unique products, indicating the regiospecificity of the reaction. Indeed, the non-formation of the other 1,5-regioisomer: may be explained: by a possible steric crowding and by electronic factors.

Experimental section
Solvents were purified by standard methods. Melting points were determined on a Buchi SMP-20 capilary apparatus and are uncorrected. TLC was carried out on a Merck 60F-254 precoated silica gel plates (0.25 mm) and column chromatography was performed with Merck silica gel (70-230 mesh). NMR spectra were recorded on a Bruker AC-300 spectrometer ( 1 H NMR at 300 MHz and 13 C NMR at 75.5 MHz) with CDCl3 as solvent and TMS as internal standard reference. Et3N was purchased from Acros. All starting protected amino esters were prepared according to the procedure. [21] In all cases, the crude amino esters was purified before use. [24] The benzohydroxyaminoyl chlorides 6(d-f) were prepared according to the literature procedures. [22] General procedure for the preparation of the new isoxazolines A magnetically stirred solution of amino esters (5a-c) and the appropriate precursor of the benzohydroxyaminoyl chlorides in dry toluene, was refluxed under nitrogen for 15 min. Et3N (2 mL) was then added and the mixture was stirred and refluxed for 48 h. After the filtration of the triethylamine hydrochloride, the solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: cyclohexane-AcOEt, 70:30).

Conclusion
We have studied the reactivity of allyl esters 5(a-c) toward acyclic benzohydroxyaminoyl chlorides 6(d-f). All cycloadducts were formed in appreciable regiospecificity and chemospecificity, giving the products in good yields. The continuous pharmaceutical interest in the isoxazoline compounds may justify further exploration of these results in the pharmacological field.