Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

The thiourea-catalyzed asymmetric synthesis of highly enantioenriched spirocyclopentaneoxindoles containing chiral amide functional groups using simple 3-substituted oxindoles and nitrovinylacetamide as starting materials was achieved successfully. This protocol features operational simplicity, high atom economy, and high catalytic asymmetry, thus representing a versatile approach to the synthesis of highly enantioenriched spirocyclopentaneoxindoles.


Results and Discussion
To establish the optimal experimental conditions for the synthesis of spirocyclopentaneoxindoles, we chose 3-substituted oxindole 1a and nitrovinylacetamide (2a) as the model substrates, and the results are summarized in Table 1. Initially, a variety of organocatalysts (a-f) were investigated in CH 2 Cl 2 at −20 °C for 12 h to evaluate their ability to promote the transformation ( Table 1, entries 1-6). When cinchona alkaloid-derived catalyst a and quinine-derived amine catalyst b were tested, however, poor yields or ee values were obtained, respectively (Table 1, entries 1 and 2). Further experiments showed that a bifunctional thiourea catalyst d was the most efficient for the synthesis of spirocyclic oxindole derivatives in good yields (80%) with excellent diastereoselectivity (8:92 dr), and moderate enantioselectivity (83% ee, Table 1, entries 3-6). Therefore, catalyst d was chosen as the optimal catalyst for further investigation ( suggested that changing the solvent had an adverse effect on the ee value, and CH 2 Cl 2 remained the best choice for this transformation (Table 1, entries 4, 7-11). Subsequently, we investigated some additives, for example, p-MeC 6 H 4 SO 3 H, trimethylsilyl chloride (TMSCl) and trifluoroacetic acid (TFA) for this catalytic system to increase the ee value of the target product; however, the use of the additives proved ineffective (Table 1, entries [15][16][17]. With the optimized reaction conditions established, we next investigated the substrate scope of 3-substituted oxindoles in this transformation with nitroolefins (Scheme 2). In general, the diverse 3-substituted oxindoles 1a-j with electron-donating, electron-withdrawing, or halide groups could undergo a smooth reaction with nitrovinylacetamide (2a) in moderate yields, good diastereoselectivity, and general enantioselectivity (3a-j). For example, the protocol showed moderate yields (75-76%), excellent diastereoselectivity (9:91-3:97 dr) and good enantio-selectivity (85-94% ee) for substrates containing 5-CH 3 or 5-OCH 3 groups (3b and 3d). Substrates carrying 5-F, 7-F, 5-Cl and 6-Cl afforded the corresponding products 3f-i in high yields (85-95%) with excellent diastereoselectivity (17:83-3:97 dr) and good enantioselectivity (76-93% ee). Surprisingly, introducing a bromo group into 6-position of the oxindole scaffold resulted in a low enantioselectivity (52% ee for 3j), although at a high yield (79%) and excellent diastereoselectivity (3:97 dr). To further extend the reaction scope, we attempted to exchange the N-Boc group of the 3-substituted oxindoles with other protecting groups, such as Bn, CH 3 or an acetyl group. The results demonstrated that only an acetyl protecting group proved to be well tolerated, providing for the efficient synthesis of spirocyclopentaneoxindoles 3k-o with moderate yields (47-74%) and excellent diastereoselectivity (9:91-2:98 dr). However, replacing the N-Boc group with an N-acetyl group on spirooxindoles had a negative effect on the stereoselectivities of the target products, probably because the N-acetyl group  decreases steric hindrance. In addition, substituents (CH 3 , Boc) at R′ and the free N-H substituted oxindole were investigated that did not give the corresponding target products (3p, 3q and 3r).
On the basis of the dual activation model proposed by Takemoto et al. [69], a plausible reaction mechanism was proposed in Scheme 3. The multifunctional organocatalyst d has a chiral scaffold including a thiourea moiety and an amino group. Both the 3-substituted oxindoles 1 and nitrovinylacetamide (2a) that participate in this reaction are activated simultaneously via multiple hydrogen bonds. In addition, the electrophilicity of the reacting carbon center of nitrovinylacetamide is likely enhanced by H-bonding, thereby enabling the Michael addition to construct a unique quaternary stereogenic center complex A which would cyclize concurrently via Henry reaction to give the product 3 and regenerates the catalyst d. The absolute configuration of 3g was determined by X-ray analysis (see Supporting Information File 1, Figure S1).

Conclusion
We have developed a highly efficient and practical strategy for a single step construction of saturated spirocyclopentaneoxin-doles containing four consecutive stereocenters and a unique quaternary stereogenic center, with good yields, and excellent diastereoselectivity and enantioselectivity using thiourea-catalyzed Michael-Henry cascade reactions. We anticipate that this reaction will simplify the synthesis of complex spirooxindoles containing multiple chiral centers with potential pharmacological properties.

Experimental
General procedure for the synthesis of products (3a-j): To a mixture of 1a-j (0.11 mmol) and 2a (0.1 mmol) in CH 2 Cl 2 (3 mL) was added catalyst d (0.01 mmol). Then the mixture was stirred at −20 °C for 12 h. After completion of the reaction, the solvent was removed by evaporation. The crude product was purified by column chromatography on silica gel to afford the desired products 3a-j.

General procedure for the synthesis of products (3k-o):
3-Substituted oxindoles 1k-o (0.11 mmol) and nitrovinylacetamide (2a, 0.1 mmol) were dissolved in 3 mL CH 2 Cl 2 , the catalyst d (0.01 mmol) was added at −10 °C for 24 h. After nitrovinylacetamide (2a) was consumed completely, the solvent was removed under vacuum. The crude product was puri-fied by column chromatography on silica gel to afford the desired products 3k-o.

Supporting Information
Supporting Information File 1 General information, experimental details, characterization data and copies of 1 H and 13 C NMR spectra, and HPLC experimental data.