Facile Synthesis of Functionalized Spiropyrrolizidine Oxindoles via a Three-Component Tandem Cycloaddition Reaction

An efficient synthesis of functionalized spiropyrrolizidine oxindoles via a three-component tandem cycloaddition has been achieved. This strategy can provide direct and rapid access to spiropyrrolizidine oxindoles in high yields (up to 99%) with excellent diastereoselectivities (up to 99:1 dr). The features of this procedure are the following: mild reaction conditions, high yields, high diastereoselectivities, one-pot procedure and operational simplicity.

Spiropyrrolizidine oxindoles are important synthetic targets and several reports of such syntheses exist [42,43]. To the best of our knowledge, however, there are no reports concerning the synthesis of spiropyrrolizidine oxindoles 4 containing two ester groups or two amide groups, which could possess some interesting biological activities. Herein, we report a three-component tandem cycloaddition reaction between substituted isatins, L-proline and maleates (maleamide) that produces such structures.

Results and Discussion
From the mechanistic perspective, the azomethine ylides, a class of powerful reagents, have emerged in a number of 1,3-dipolar cycloaddition reactions. In combination with the experiences in previous work, we envisaged that an azomethine ylide could be generated in situ from isatin (1a) and L-proline (2), and then trapped with dimethyl maleate (3a) acting as dipolarophile to afford spiropyrrolizidine oxindole 4a. Hence, the 1,3-dipolar cycloaddition reaction would be facilitated (Scheme 1).

Scheme 1.
Possible reaction mechanism for the synthesis of spiropyrrolidine oxindole.
In light of the above considerations, the reaction in methanol at 60 °C of dimethyl maleate with azomethine ylide (generated in situ by decarboxylative condensation of isatin and L-proline) was examined. After 3 h, the expected adduct 4a was obtained in 87% yield (Table 1, entry 1). We were pleased to see that our reaction afforded the adduct 4a with excellent diastereoselectivity (99:1, determined by 1 H-NMR). The structure of 4a was further confirmed by a single crystal X-ray crystallographic study (Figure 1) [14]. The ORTEP diagram of 4a shows that: (i) the pair of linked pyrrole rings of pyrrolizidine nucleus adopts an envelope-like conformation, (ii) H-3, H-4 and H-5 are all cis and (iii) the two carbonyls linked to C-2 and C-3 of 4a have a trans stereochemical relationship. This can be explained by the fact that the corresponding endo transition state (A) would require less free energy of activation than the exo transition state (B) leading to 4a′ as the latter would result in electrostatic repulsion between the cis carbonyls increasing the free energy of activation (Scheme 2). Therefore, the relative configuration of 4a was assigned as shown in Table 1.  To improve the yield, efforts were made to optimize other reaction parameters including solvents and reaction temperatures. Thus, the reaction was studied in different solvents that included ethanol, isopropanol, acetonitrile, chloroform, tetrahydrofuran and 1,4-dioxane (Table 1, entries 2-7). To our satisfaction, the reaction in 1,4-dioxane led to the desired product in almost quantitative yield (99%) and maintained stereoselectivity (Table 1, entry 7), while ethanol as solvent gave the product in only 63% yield (Table 1, entry 2). In general, reactions carried out in aprotic solvents were better yielding than those in protic solvents. Temperature influenced the rate of the reaction. Elevating the reaction temperature resulted in a high reactivity and the reaction time was shortened to 45 min (Table 1, entry 9). Based on the consideration of reaction time and yield, the optimized conditions were those shown in Table 1, entry 7.
To show the general nature of the reaction, isatin bearing different substituents and L-proline were reacted with maleates (maleamide) under optimized conditions. Various functional groups appeared to be well tolerated and gave the corresponding spiropyrrolizidine oxindoles in moderate to good yields (51-99%) with excellent diastereoselectivities (up to 99:1). The results are summarized in Table 2. For dimethyl maleate, the results showed that the reaction took place with excellent diastereo-selectivities of up to 99:1, regardless of the electronic and steric nature of the substituted isatins. However, the yields of the reaction were affected by the substitutent group on the isatins ( Table 2, entries 1-6). 5-Bromoisatin resulted in low to 71% yield, with an extention of the reaction time to 8 h ( Table 2, entry 3). The oxindole core may also be modified. Thus, the N-protecting group may be changed as well. Incorporating different protecting groups on the N1 of oxindole had little effects on reactivity and diastereoselectivity (Table 2, entries 7-8). For the diethyl maleate, a similar phenomenon was observed. Substituents on the isatins influenced the diastereoselectivities only slightly, but affected the yields to a greater extent ( Table 2, entries 9-16). Generally, isatins with electron-withdrawing groups gave lower yields than those with electron-donating groups. However, when we further expanded the substrate scope to maleamide ( Table 2, entries [17][18], the corresponding products were obtained in moderate yields (51-64%). The stereochemistry of the other products was assigned by analogy to the relative configuration of 4a.

General
All chemicals were obtained from commercial sources and used without further purification. Column chromatography was carried out on silica gel (300-400 mesh, Qingdao Marine Chemical Ltd., Qingdao, China). Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates. 1 H-NMR and 13 C-NMR spectra were recorded on Varian Gemini 400 Bruker AVII-400 or Bruker AVII-600 spectrometers. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constants (Hz), integration. Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as internal standard. Mass Spectra (MS) were measured by 3200 Q TRAP LC/MS/MS utilizing electrospray ionization (ESI).

Experimental Procedures
A mixture of isatin (0.2 mmol), L-proline (1 eq.), dimethyl maleate (1 eq.) in 1,4-dioxane (1 mL) was stirred for 3 h at 60 °C. After completion of the reaction (TLC), the solvent was removed under vacuum. The crude product was subjected to column chromatography on silica gel using CH 2 Cl 2 -ethyl acetate (2:1) as the eluent to give 4a (60 mg, 87% yield). Compounds 4b-r were synthesized by a similar procedure as described for compound 4a. For the separation of these compounds, the eluent of silica gel column chromatography consisted of appropriate mixtures of CH 2 Cl 2 and ethyl acetate or CH 2 Cl 2 and MeOH.

Conclusions
In this work, we have developed an efficient method for the synthesis of potentially biologically active spiropyrrolizidine oxindoles via a three-component 1,3-dipolar cycloaddition reaction. A range of spiropyrrolizidine oxindoles bearing two ester or two amide groups were obtained in high yields (up to 99%) with excellent diastereoselectivities (up to 99:1 dr). The methodology is rapid, simple, and