Protecting-group directed stereospecific organocatalytic [3+2] cycloadditions: a facile access to chiral spirocyclic oxindoles

An efficient organocatalytic [3+2] cycloaddition between isocyanides and methyleneindolinones, with simultaneous formation of two quaternary stereocenters, for the rapid construction of dihydrospiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural diversity was developed. Furthermore, different protecting group on the nitrogen atom of methyleneindolenones gave rise to a different major diastereoisomer, suggesting a new avenue of great importance to medicinal chemistry and diversity-oriented synthesis.


Scheme 1. Proposed strategy for construction of spiro[pyrrolidin-3,3′-oxindole] skeletons by [3+2] cycloaddition between isocyanides and methyleneindolinones.
In this communication, the discovery of the first asymmetric organocatalytic [3+2] cycloaddition between isocyanide and methyleneindolinone with simultaneously formation of two quaternary and one tertiary stereocenters is reported for the rapid construction of dihydrospiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural diversity.Furthermore, different protecting group gave rise to different major diastereoisomer, which suggested a new avenue of great importance to medicinal chemistry and diversity-oriented synthesis.

Results and Discussion
The initial optimization began with the addition of isocyanide 1a (1.5 equiv) to methyleneindolinone 2a in CH2Cl2 in the presence of commercially available quinine (catalyst I, 10 mol%) at room temperature.Although the reaction proceeded smoothly, the major product was separated from a 1.1 to 1 mixture of diastereoisomers in 43% yield with a poor enantioselectivity (32% ee, Table 1, entry 1).Several other cinchona alkaloids were tested (catalysts II and III) under the same condition, however, the yield and selectivity were generally not good (Table 1, entries 2 and 3).Notably, a significant improvement in both diastereo-and enantioselectivity was observed when cinchona alkaloids containing thiourea scaffolds were screened (Table 1, entries 4-7).The reactions fully completed within 2 hours and the highest ee was achieved using catalyst VI, accomplished with good yield (76%) and catalyst VII produced the opposite enantiomer with comparable ee value.A subsequent solvent screening revealed that nonpolar solvents are beneficial to this type of reaction, as slight increase in enantioselectivity and yield was observed in toluene (Table 1, entry 8).There was somewhat drop in ee when only 1.0 equiv of isocyanide 1a was used (Table 1, entry 10).Decreasing the reaction temperature prolonged the reaction time with no improvement in either enantioselectivity or yield (Table 1, entry 11).Finally, 5 mol% catalyst loading was found to be better for obtaining high yield and excellent enantioselectivity (Table 1, entries 12 and 13).
With the optimized condition in hand, the scope of Boc-protected methyleneindolinones was investigated (Table 2).The presence of both electron withdrawing group and donating group at the indolinone moiety was all tolerated to afford more than 99% ee (Table 2, entries 1-5).Methyleneindolinone derivatives bearing various substituents at the C-C double bond also participated in the direct [3+2] cycloaddition reactions.Excellent enantioselectivity in up to >99% ee was generally obtained with ester substituents on the C-C double bond (Table 2, entries 6 and 7).It was noteworthy that a slight drop in ee (only 98%) with prolonged reaction time was observed as the ester substituents were replaced by ketones (Table 2, entries 8-10).The absolute configuration of Boc-protected product 3c was determined by X-ray crystallography (Figure 3).Table 1.Catalyst screening and optimization of cycloaddition reaction conditions a a All reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and methyleneindolinone 2a (0.1 mmol, 1.0 equiv) with 10 mol% of catalyst at 23 C.b Isolated yield (major isomer).c dr determined by crude 1 H-NMR; the relative configuration of the minor diastereoisomer corresponds to that of compound 5a (see Table 3).d ee was determined by chiral HPLC.e Only 1.0 equivalent 1a was used.f The reaction was conducted at 0 C.g 5 mol% catalyst was used.In the course of cycloaddition between isocyanide and Boc-protected methyleneindolinones, besides the isolated major isomer, some minor compound was also observed in small amount.Since the spiro[indoline-3,3′-pyrrolidine] core is of promising biological properties, there is a high possibility that the minor stereoisomers process unique bioactivities.Therefore, it is a very great importance for "diversity-oriented synthesis", 47 if the minor isomers could be formed as major products.
Based on the previous reports 48 and our comprehension of this cycloaddition reaction, we anticipated that changing the electronic and steric properties of the methyleneindolinones by modification of the protecting group on nitrogen atom might be a promising approach to affect the diastereoselectivity. Remarkably, a new diastereoisomer 49 was obtained as major product by simply replacing the protecting Boc-group with benzyl group.Several methyleneindolinones were selected for investigation of the generality of this approach (Table 3).Good yields and excellent enantioselectivities were obtained with methyleneindolinones bearing various substituents on the indolinone moiety and C-C double bond.Compared with the Boc-protected substrates, the reaction with the Bn-protecting group is generally slower and needs double catalyst loading (10 mol%).
Although the electronic and steric properties of the substrates pay a crucial role to the stereoselectivity of cycloaddition reaction, from the results of this specific reaction, the steric hindrance of protecting group is the determinant factor for high diastereoselectivity.For further understanding the inherent insight, we obtained the structure of a Bn-protected substrate by Xray crystallography (see the Supporting material).As one face may be blocked by the presence of protecting group, leaving one site open for the cycloaddition.Thus, a catalytic activation mode of the cycloaddtion reactions was proposed (Figure 4).Table 2. Boc-protected substrates scope of the cycloaddition reactions a a All reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and methyleneindolinone 2a-2J (0.1 mmol, 1 equiv) with 5 mol% of catalyst VI at 23 C.b Isolated yield (major isomer).c dr determined by crude 1 H-NMR.d ee was determined by chiral HPLC.Further exploration of substrate scope was focused on the variation of isocyanides.Two more the methyl and benzyl isocyano-esters (1b and 1c) were tested as typical examples (Scheme 2).Gratifyingly, both reactions proceeded smoothly in high yield and enantioselectivity, further illustrating the validity and generality of this direct asymmetric cycloaddition.

Conclusions
An asymmetric organocatalytic [3+2] cycloaddition of isocyanide and methyleneindolinone has been developed in good yield and excellent enantioselectivity, tolerating a broad range of substrates.The approach was associated with the formation of two quaternary and one tertiary carbon stereogenic centers, providing a highly stereoselective solution to the complex spiro[pyrrolilin-

Experimental Section
General.Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 precoated silica gel plate (0.2 mm thickness).Subsequent to elution, plates were visualized using UV radiation (254 nm) on Spectroline Model ENF-24061/F at 254 nm.Further visualization was possible by staining with basic solution of potassium permanganate or acidic solution of ceric molybdate.Flash chromatography was performed using Merck silica gel 60 with freshly distilled solvents.Columns were typically packed as slurry and equilibrated with the appropriate solvent system prior to use.Proton nuclear magnetic resonance spectra ( 1 H NMR) were recorded on Bruker AMX 400 spectrophotometer (CDCl3 as solvent).Chemical shifts for 1 H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet).were given as: s (singlet), d (doublet), t (triplet), dd (double of doublet) or m (multiplets).The number of protons (n) for a given resonance is indicated by nH.Coupling constants are reported as a J value in Hz.Carbon nuclear magnetic resonance spectra ( 13 C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.0, triplet).Enantioselectivities were determined by High performance liquid chromatography (HPLC) analysis employing a Daicel Chiralpak AD-H or OD-H.Optical rotations were measured in CH2Cl2 on a Schmidt + Haensdch polarimeter (Polartronic MH8) with a 1.0 mL cell (c given in g/100 mL).Absolute configuration of the products was determined by X-ray.High resolution mass spectrometry (HRMS) was recorded on Finnigan MAT 95×P spectrometer.

Figure 1 .
Figure 1.Some examples of natural occurring and biologically active spirocyclic oxindoles.

Figure 4 .
Figure 4. Proposed activation mode of the catalyst and substrates.

h
Catalyst loading was 2 mol%.

Table 3 .
Scope of the [3+2] cycloaddition with Bn-protected substrates a a All reactions were carried out by using isocyanide 1a (0.15 mmol, 1.5 equiv) and methyleneindolinone 4a-4e (0.1 mmol, 1 equiv) with 10 mol% of catalyst VI at 23 C.b Isolated yield.(Crude 1 H-NMR displayed only one major isomer.However, the product is not very stable, which decreased the isolated yield.) c ee was determined by chiral HPLC.
achieved by choosing different protecting groups on the nitrogen atom of methyleneindolinones.The success of this strategy opens up new perspectives in the construction of complex spiro[pyrrolidin-3,3′-oxindole] structure for a rapid access to biologically and pharmaceutically active candidates.