1,3-Dipolar cycloadditions of D-erythrose-and D-threose-derived nitrones to maleimides

The nitrones derived from cyclic acetals of D-erythrose 1a,b and D-threose 2a,b react with N - phenylmaleimide ( 3 ) to afford the corresponding diastereomeric isoxazolidines. The stereoselectivity is dependent on the steric hindrance of the nitrone. In the case of D-erythro - derived nitrones 1a,b the cycloaddition is exo -selective. The major products are in the C-3/C-4 erythro - and C-3/C-3a trans -configuration. This finding can be rationalized by a less hindered exo -attack of the ( Z )-nitrone in an antiperiplanar manner with respect to the largest group of the cyclic acetal. The cycloaddition to the chiral maleimides 12 and 13 is less stereoselective.


Introduction
The nitrone -olefin 1,3-dipolar cycloaddition is a powerful reaction in that it can create as many as three new contiguous stereogenic centers in a single step. 1 Based on an evaluation of the nitrone cycloaddition, it was felt that the configuration of these new centers could be influenced if the reaction system was properly designed. 2Regio-and stereoselective nitrone cycloaddition, followed by reduction of the N-O bond to produce both an amino and a hydroxy functionality, allows the synthesis of many products of potential interest. 3ver the years, nitrones have become important building blocks in organic synthesis 1,4 However, in spite of their well-documented utility there are only scattered reports dealing with the preparation of nitrones with a chiral C-substituent. 5,6With the goal of developing a simple route to polyhydroxylated derivatives of pyrrolizidines, 7 which have been shown to display antiviral activity, 8 via an asymmetric 1,3-dipolar cycloaddition we have recently published the preparation of new D-erythrose-and D-threose-derived nitrones and the stereoselectivity of their cycloadditions to styrene. 9,10n this paper we report the stereoselectivity of the cycloaddition of chiral sugar-derived nitrones 1a,b and 2a,b with N-phenylmaleimide (3) and the chiral maleimides 12 and 13.

Results and Discussion
The diastereomerically pure (Z)-nitrones 1a,b and 2a,b were subjected to 1,3-dipolar cycloaddition reactions.Our task was to study the asymmetric induction from the nitrone part.There are four possible products; cisand trans-isomers from antiand syn-attack (Scheme 1).With each of the nitrones the reaction proceeded smoothly in high yields.

Scheme 1
The structure assignments of the products are based on straightforward analysis of NMR spectra.The stereochemistry of the cycloadducts was deduced by their NOE experiments.The most important and decisive information obtained from these experiments is the presence or absence of the NOE interaction between the protons 3-H/3a-H and 6a-H/3-H in the corresponding exoand endo-cycloadducts, respectively.Finally, the relative 3-C/4-C erythroconfiguration in the isolated adducts was assigned by comparison with the analogue prepared by the cycloaddition from nitrone 1a with styrene, the structure of which was elucidated by X-ray analysis. 10The ratio of diastereoisomers was determined from 13 C NMR spectra by integration of the peaks of the 3a-C signals of the isoxazolidine products.
The cycloadditions were first carried out in boiling toluene with N-phenylmaleimide (3).In the case of D-erythro-derived nitrones 1a,b only two diastereoisomers, erythro-trans 4a,b and threo-trans 5a,b were formed (entries 1 and 2, Table 1).3,3a-cis-Disubstituted endo-adducts 6 and 7 were not detected in the crude reaction mixture by NMR spectra (Scheme 1).The cycloadducts 4a,b and 5a were separated by column chromatography.The analysis of product configuration indicates that 4a,b and 5a,b arise from a cycloaddition which has occurred on the more sterically accessible face of the nitrone, via an exo-transition state with syn periplanar relationship of the N-phenyl and N-benzyl group.Dipolar cycloaddition of C-α-alkoxy-substituted nitrones have been shown to occur preferentially via transition states in which the developing carbon-carbon bond avoids steric interaction with the more bulky group. 2,10,11We consider that both isoxazolidines 4 and 5 result from a 100% exo-attack of the dipolarophile maleimide (3) on the (Z)-nitrone 1a,b, because the corresponding (E)-nitrones were not detected by 1 H NMR.There was no thermal interconversion between the prepared adducts in refluxing toluene, thus indicating that the cycloaddition proceeded irreversibly under the reaction conditions to give the kinetically controlled products 4 and 5, respectively.Such total exo selectivity may be ascribed to the steric interaction in the transition state between the phenyl group of maleimide (3) and the heterocyclic moiety of the nitrone 1a,b in corresponding endo-transition state that would lead to the cycloadducts 6a,b and 7a,b.

Figure 1
The diastereofacial selectivities of the above-mentioned cycloadditions are highly dependent on the structures of nitrone and maleimide.While the reactions employing D-erythro-derived nitrones 1a,b (Entries 1-3, Table 1) gave poor anti-selectivities, the reactions using D-threo- derived nitrones 2a,b gave good stereoselectivities (entries 4-6, Table 1).The lowest erythro:threo ratio of 50:50 has been observed in the case of D-erythro-derived nitrone 1a (Entry 1, Table 1).These differences in anti/syn-selectivity can be rationalized by considering the transition states in the cycloaddition (Figure 1).Since the cycloadditions proceed from (Z)nitrone preferentially via the less hindered exo-transition state and in an antiperiplanar manner with respect to the largest group of the heterocyclic acetal, the methyl substituent in the nitrone is oriented in the syn/anti-position relative to the maleimide 3. Accordingly, the use of D-threoderived nitrones 2a and 2b having the methyl group in the axial position gave better selectivities.The diastereofacial selectivities observed are comparable to the previously published results obtained by the cycloadditions of these nitrones with styrene10 as well as to results reported for a cyclic nitrone with N-benzylmaleimide. 12ext, the nitrones 1a,b and 2a were treated with chiral maleimides 12 and 13 (Schemes 2 and 3).The exo-product, erythro-trans 14, 18, and 22 was isolated as the major isomer in each case.The diastereofacial selectivities of the cycloaddition to chiral maleimides 12 and 13 are only moderate (Entries 7-10, Table 1).Although the chiral maleimides 12 and 13 are enantiomers, the product ratios of formed isoxazolidines resulting from the cycloaddition of the D-erythro-derived nitrone 1a are not similar.The stereogenic centre in chiral maleimides has an influence on the trans:cis ratio of the isomers formed (68:32 and 93:7, Entries 7 and 8, Table 1).On the other hand, in the reaction of the protected D-erythro derived nitrone 1b with the chiral maleimide 13 only two exo-diastereoisomers, erythro-trans 18b and threo-trans 19b were formed (Entry 9, Table 1).

Scheme 2
It is noteworthy that our attempts to accelerate the cycloaddition by microwave irradiation were successful.Indeed, microwave irradiation dramatically decreased the reaction times of the cycloadditions.For example, in the case of the cycloaddition of nitrone 1b with dipolarophile 3, the reaction time decreased from 11 h to 8 min.Moreover, microwave irradiation could even reverse the ratio of erythro-trans / erythro-cis adducts from 63:37 to 39:55 for 1b (Entries 2 and 3, Table 1).To the best of our knowledge this reversal of stereoselectivity of the nitrone cycloaddition using microwave irradiation is a very rare phenomenon.On the other hand, in the case of the cycloaddition of nitrone 2b to imide 3 microwave irradiation only slightly changed the ratio of diastereomers (Entry 6, Table 1) while the reaction time decreased from 3 h to 10 min.

Scheme 3
Experimental Section General Procedures.All starting materials and reagents are commercially available (Fluka, Merck or Avocado) and were used without further purification.Solvents were dried before use.
Thin-layer chromatography (TLC, on aluminium plates coated with silica 60F 254 , 0.25 mm thickness, Merck) was used for monitoring of reaction courses; eluents are given in the text.For column chromatography the flash chromatography technique was employed using silica 60 (0.040-0.063 mm, Merck).Melting points (mp) were determined on a Kofler hot plate apparatus and are uncorrected.Elemental analyses were performed by the microanalysis service of the Department of Analytical Chemistry, Slovak University of Technology, Bratislava.The 1 H and 13 C NMR spectra of deuterochloroform solutions were obtained using Varian VXR 300 (300 MHz) and Bruker DRX-400 (400 MHz) instruments, tetramethylsilane being the internal reference.Optical rotations [α] were measured on an IBZ Messtechnik Polar-LµP polarimeter at the sodium D line (589 nm) using a 1 dm cell with chloroform as solvent.The nitrones 1a,b and 2a,b were prepared from the corresponding aldehydes by the reaction with N-benzylhydroxylamine 13 in dichloromethane in the presence of anhydrous magnesium sulfate according to the procedure used in the literature for the preparation of chiral N-benzyl nitrones. 13reviously described methods were used to prepare the corresponding aldehydes [15][16][17][18] and maleimides. 19