1,3-Dipolar Cycloaddition Reactions: Diastereoselective Synthesis of Pyrrolo- Isoxazolidine Derivatives

An atom economic and facile synthesis of novel diastereomeric isoxazolidines with high selectivity has been achieved via 1,3-dipolar cycloaddition of C, N-diphenylnitrones 1 with N-aryl maleimides 2. The structure and steric configuration of the adducts have been assigned on the basis of IR, 1H-NMR, 1H,1H-COSY, NOESY, 13C-NMR and mass spectroscopy. The π-π stacking interactions between maleimide’s and nitrone’s aromatic rings during the 1,3dipolar cycloaddition and the position of the substituents present on the C-phenyl ring of the C,N-diphenylnitrones were assumed to control the exo-endo selectivity of the reaction.


Introduction
Cycloaddition reactions are atom-economic processes that are among the most powerful synthetic strategies for the preparation of functionalized cyclic structures [1]. In particular, the enantioselective 1,3-dipolar cycloaddition reaction (DCR) of an alkene with a nitrone can lead to the construction of up to three contiguous asymmetric carbon centres. The resulting fivemembered isoxazolidine derivatives may be converted into amino alcohols, precursors to biologically important amino acids [2], alkaloids [3,4] or β-lactams [5] and thus serve as key synthetic intermediates [6]. Nitrone functionality embedded in the cyclic systems has been extensively utilized to incorporate and elaborate isoxazolidine moieties so widespread in nature [7][8][9][10][11]. Nitrone cycloaddition reaction, by virtue of its regio-, stereo-, face-, and chemo-selectivity, has etched an important place in organic synthesis. One more reason for the success of the synthetic application of nitrones is that, contrary to the majority of other 1,3dipoles, most nitrones are stable compounds that do not require in situ formation. The ability to utilize nitrone cycloaddition in organic synthesis depends heavily on understanding the factors that determine the stereochemistry of the reaction. Considerable regio-and stereochemical control can be exerted in these cycloadditions by choosing appropriate substituents on the dipole and the dipolarophiles [12][13][14][15][16][17][18][19][20]. In our work, we investigated the effects of ortho-substituents on C-phenyl group of nitrones on the exo-endo selectivity of cycloaddition reactions with variously substituted maleimides. This could ensure an entry to the control of the stereochemistry of cycloaddition, where the π-π stacking interactions may play a crucial role.
The stereochemical assignment of the these diastereomers was made on the basis 1 H-NMR, 1 H, 1 H-COSY and NOESY spectral data which revealed the coupling patterns for both the diastereomers that allowed for the differentiation between the two molecules using their obtained spectra. The isomers showing C 3 -H and C 6a -H as doublets and C 3a -H as doublet of doublet on coupling with both protons C 3 -H and C 6a -H were assigned as cis geometry and the isomers showing C 3 -H as singlet, C 3a -H and C 6a -H as doublets in their 1 H-NMR spectra were assigned as trans geometry.
In their IR spectra these derivatives exhibit a strong absorption band (ν max ) in the range 1712-1717 cm -1 and a shoulder band in the range 1746-1792 cm -1 due to imide carbonyl groups. In the 1 H-NMR spectra of 3a-B, a doublet at δ 4.09 with J= 7.38 Hz was assigned to C 3a -H, a doublet at δ 5.17 with J= 7.44 Hz was assigned to C 6a -H, a singlet at δ 5.95 was assigned to C 3 -H proton respectively. However, in the 1 H-NMR spectra of 3a-A, a doublet of doublet at δ 4.07 with J= 9.04 Hz and 7.92 Hz assigned to C 3a -H, a doublet at δ 4.91 with J= 9.04 Hz has been assigned to C 3 -H, a doublet at δ 5.29 with J= 7.88 Hz has been assigned to C 6a -H.
In 1 H, 1 H-COSY spectra of cis isomer 3a-A (Figure 1), the presence    H 6a in both the isomers shows the same planarity of these protons in these isomers.
In the NOESY spectra of cis isomer 3a-A (  In the 13 C-NMR spectrum of 3a-A signal at δ 55.78 was assigned to C-3a, while signals at δ 66.74 and 77.87 were assigned to carbons C-6a and C-3 respectively. Suitable signals due to aromatic carbons were assigned to the region of δ 113.71-149.02. The two carbonyl carbons of succinamide ring C-4 and C-6 appeared at δ 172.73 and 173.88 respectively. While in the 13 C-NMR spectrum of 3a-B signal at δ 55.73 was assigned to C-3a, while signals at δ 66.83 and 77.69 were assigned to carbons C-6a and C-3 respectively. Suitable signals due to aromatic carbons were assigned to the region of δ 113.60-148.86. The two carbonyl carbons of succinamide ring C-4 and C-6 appeared at δ 172.49 and 173.55 respectively. The preferred orientation of the azomethine N-oxides at the transition state seems to be 'anti' one where steric interactions are minimum. So as the dipole and dipolarophile approach each other there are π-π interactions between the two substrates. This more favored orientation of the azomethine N-oxide results in the formation of cis isomer as the major one, perhaps due to the steric requirement alone. From a study of the Drieding models of the cisisomers ( Figure 7) it has been found that this is the most favored conformation for isomer cis (A) as non-bonded steric interaction are completely absent in this transition state. The trans-isomer (B) also arises from the 'anti' form of the azomethine N-oxide but in this case the attack by the dipolarophile maleimide occurs from the azomethine N-oxide molecule. In the transition state accumulation of the double bonds again plays a dominant role. In this case, N-phenyl nucleus of the dipole rather than the C-phenyl ring comes in a plane nearly parallel to the unsaturation of the carbonyl group of the imide, since these are separated by two atoms (O and C on one side and C and C atoms on the other) rather than by one atom as in the previous transition state, this secondary interaction is, therefore smaller in this transition state, which leads to the formation of the minor trans-isomer B (Figure 8). Thus cis isomer should predominate the trans isomer.
But the cis/trans selectivity in these reactions is primarily controlled by the substituent on C-styryl moiety. In case of o-Cl and o-OH groups on C-phenyl ring, the cis-trans isomeric ratio is found to be the reverse. In these cases the closer approach of lone pairs of ortho groups attached to the C-phenyl ring to the lone pairs of oxygen atom of carbonyl moiety leads to repulsion and thus leading to the dominance of trans over the cis isomer (Figure 9, 10).

Conclusion
In conclusion, we have successfully developed the stereoselective version of synthetically significant pyrrolo-isoxazolidine ring systems through 1,3-dipolar cycloaddition reactions. It was observed that the azometine N-oxides, added stereo-and regioselectively across the double bonds of the dipolarophiles to give novel isoxazolidines which indicated the high exo-diastereoselectivity due to the steric interactions present in endo-type transition state of these orthosubstituted derivatives.

Experimental Chemistry
General: Unless otherwise indicated, all common reagents were used as obtained from commercial suppliers (Sigma Aldrich) without further purification and the solvents were dried before use. All melting points were recorded on Gallen-Kamp apparatus and are uncorrected. IR spectra were recorded on a Perkin Elmer RXIFT infrared spectrophotometer (manufactured at Buckinghamshire, England) using KBr pellets. 1 H-NMR, 1 H, 1 H-COSY and NOESY were recorded at 400 MHz on BRUKER spectrometer (manufactured at Fallanden, Switzerland) using tetramethylsilane (TMS) as internal standard. The 13 C-NMR spectra were recorded at 100-MHz on BRUKER spectrometer using TMS as internal standard. Mass spectra were recorded on Waters Micromass Q-T of Micro (ESI) spectrometer (manufactured at Vernon Hills, USA). Elemental analysis was carried out using Elementar Vario MICRO cube CHN analyzer (Frankfurt, Germany). Thin-layer chromatography (TLC) analysis was carried out on glass plates coated with silica gel-G (Loba Chemie) suspended in methanolchloroform. Column chromatography was performed using silica gel (60-120 mesh, Loba Chemie).

General Procedure for Synthesis of Azomethine N-Oxide:
The mixture of nitrobenzene (4.2 mL, 41 mmol) and ammonium chloride (2.5 g, 46 mmol) in 100 mL of water was stirred for one hour with slow addition of zinc dust (5.9 g, 83 mmol) with the help of a mechanical stirrer. The rate of addition of zinc dust was such that rise in temperature was not more than 65-70 °C. After complete addition of zinc, the stirring was continued for further 15 minutes to complete the reduction which was observed by decrease in temperature of the reaction mixture. The resulting solution was filtered and washed with warm water (100mL). The filtrate was extracted with chloroform to which was added stoichiometric amount of aromatic aldehyde and then stirred the mixture till the solid precipitated out (Scheme 1). The synthesis of product was confirmed by TLC and further by recording the melting points of the nitrones obtained.
General Procedure for Synthesis of Maleimide: Equimolar quantities of p-substituted aniline and maleic anhydride were stirred in toluene at room temperature for one hour to yield maleimic acid. The maleimic acid thus obtained was further cyclised to maleimide (Scheme 2) in acetic anhydride in the presence of anhydrous sodium acetate by refluxing on hot water bath for one and half hour and then pouring the contents in ice cold water and keeping it overnight to afford the solid which was filtered and washed with water to give the maleimide 2.