Diastereodivergent synthesis of fully disubstituted spiro[indoline-3,2′-pyrrolidin]-2-ones via tuneable Lewis base/Brønsted base-promoted (3 + 2) cycloadditions

Abstract

Herein we report a diastereodivergent synthesis of fully disubstituted spiro[indoline-3,2′-pyrrolidin]-2-ones through base-promoted (3 + 2) cycloadditions. Importantly, the catalysts are found to have full control over the configuration of the stereocenters. When a Lewis base (PCy₃) is used as a catalyst, good yields and excellent diastereoselectivities are obtained, regardless of the properties of the substituents, whereas spiro[indoline-3,2′-pyrrolidin]-2-ones of a different diastereoisomer are produced in good yields when a Brønsted base (K₂CO₃) is used. ESI-MS experiments proved the existence of key zwitterionic intermediates.

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Spiro[indoline-3,2′-pyrrolidin]-2-ones are found as core motifs in an array of biologically active natural products, pharmaceuticals, and their analogues.¹ Their absolute and relative configurations have been proven to play a key role in the biological activity of spirocyclic compounds. As such, the diastereodivergent synthesis of a target spirocyclic compound not only results in the formation of spirocyclic compounds with varied biological activities but also allows the exploration of configuration–activity relationships.² Nevertheless, precise access to different diastereomers of the product is incredibly difficult because diastereochemical behaviour is primarily dominated by the inherent structural and stereoelectronic nature of substrates. Most of the strategies currently available rely on using different catalysts, switching of solvents or additives, and using dual catalysis to selectively access complementary diastereomers.³ Despite all this, utilizing two distinct catalysts for the complete diastereoisomeric control of products bearing multiple stereocenters is highly desired but remains an unmet synthetic challenge.⁴

Lewis base catalysis, which mainly includes tertiary phosphine and amine catalysts, has recently become one of the most powerful methods for the chemoselective synthesis of cyclic and heterocyclic compounds.⁵ For example, in 2011, Kwon and Guo reported allene-dependent (3 + 2), (3 + 3), (4 + 3), and (3 + 2 + 3) annulations that were carried out by changing the substrates.⁶ In 2016, Lu and colleagues described phosphine-catalyzed regiodivergent γ-additions wherein C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates were realized by using different phosphine catalysts.⁷ In 2017, Huang and co-workers achieved the divergent synthesis of hydropyridine derivatives via Lewis base mediated (4 + 2) cyclizations.⁸ More recently, our group developed phosphine-catalyzed enantioselective (4 + 2) annulation reactions of γ-benzyl allenoates wherein two diastereoisomeric phosphine catalysts functioned as pseudoenantiomers, providing a wide range of 3,3′-spirocyclic oxindoles with opposite absolute configurations.⁹ Although numerous advances have been made in controlling the chemoselectivity and enantioselectivity of products, the divergent synthesis of two different diastereomers from identical starting materials in the field of Lewis base catalysis remains highly desirable.

Phosphine-catalyzed annulation reactions of electron-deficient olefins with imines offer a very reliable strategy for the construction of valuable heterocycles.¹⁰ With regard to the reaction mechanism, the nucleophilic addition of a phosphine catalyst to the electrophilic β-carbon of electron-deficient olefin results in the generation of a zwitterionic intermediate, which subsequent undergoes a Michael addition reaction with imine (Scheme 1A). In 2020, Zhou and co-workers reported a phosphine-catalyzed cascade annulation reaction between aldimine esters and δ-acetoxy allenoates, which involved a different reaction mechanism (Scheme 1B).¹¹ Inspired by this, we envisioned that a change in the reaction pathway might regulate the relative configuration and steric hindrance of the transient state, and the divergent synthesis of two different diastereomers from identical starting materials could thus be realized. Recently, we developed a new conjugated diene derived from β,γ-unsaturated α-ketoester, which produced a new zwitterionic intermediate and might lead to the unpredictable prospect of a new reaction discovery.¹² In addition, N-2,2,2-trifluoroethylisatin ketimines have been employed as azomethine ylide precursors undergoing a cycloaddition reaction with electron-deficient alkenes for the construction of spirocyclic oxindole derivatives bearing a CF₃ group.¹³ Herein, we wish to report our research on this subject. This report shows that we are the first to realize the divergent synthesis of two different diastereomers from identical starting materials by applying a different achiral Lewis base (PCy₃)/Brønsted base (K₂CO₃) catalytic system (Scheme 1C).

Scheme 1 Strategy for the divergent synthesis of two different diastereomers.

We began our study by choosing N-2,2,2-trifluoroethylisatin ketimine 1a with conjugated diene 2a as the model substrates. The screening was initiated by the examination of different phosphine catalysts (Table 1 entries 1–5). The result showed that PCy₃ was the optimal catalyst, giving the products endo-3a in 21% yield and exo′-4a in 15% yield, respectively. Subsequently, the influence of the solvent was examined, and acetonitrile showed the best diastereoselectivity (Table 1, entries 6–9). Upon prolonging the reaction time to 60 h, the product was obtained in an increased yield of 59% with excellent diastereoselectivity (Table 1, entry 10). It is noteworthy that the best yield of endo-3a was observed when PCy₃ (25 mol%) was used (66% yield; Table 1, entry 11). Tertiary amine catalysts were also examined, and it was found that DBU was a poor catalyst (Table 1, entries 12–14). Interestingly, when Brønsted bases (Cs₂CO₃ and K₂CO₃) were used, the diastereoisomer exo′-4a was obtained as the major product (Table 1, entries 15 and 16). When the solvent was changed to CHCl₃ in the presence of K₂CO₃, the diastereoselectivity was fully reversed, producing only the diastereoisomer exo′-4a in 78% yield (Table 1, entry 17). Finally, an improvement in the yield (90%) was obtained when the loading of the Brønsted base was increased to 100 mol% (Table 1, entries 17–19).

Table 1 Optimization of the reaction conditions^a

Entry	Cat. (mol %)	Solvent	Yield^b (%)
			3a (%)	4a (%)
a Reaction conditions: unless otherwise noted, the reactions were conducted with 1a (0.10 mmol) and 2a (0.15 mmol) in 1.0 mL of solvent for 48 h, PCy3 = tricyclohexyl phosphine. b Isolated yield. dr > 20 : 1; the two isomers could be isolated by flash column chromatography. c Reaction time: 60 h.
1	PPh3 (20)	THF	NR	NR
2	PBu3 (20)	THF	14	8
3	PCy3 (20)	THF	21	15
4	PEtPh2 (20)	THF	20	40
5	PPhEt2 (20)	THF	24	24
6	PCy3 (20)	MeCN	36	—
7	PCy3 (20)	CHCl3	NR	NR
8	PCy3 (20)	EA	NR	NR
9	PCy3 (20)	i-PrOH	64	28
10^c	PCy3 (20)	MeCN	59	—
11^c	PCy3 (25)	MeCN	66	—
12	DABCO (20)	THF	21	61
13	DMAP (20)	THF	16	30
14	DBU (20)	THF	NR	NR
15	Cs2CO3 (20)	THF	29	33
16	K2CO3 (20)	THF	26	55
17	K2CO3 (20)	CHCl3	—	78
18	K2CO3 (50)	CHCl3	—	87
19	K2CO3 (100)	CHCl3	—	90

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Having established the optimized reaction conditions, we explored the substrate scope of the phosphine-catalyzed diastereoselective (3 + 2) annulation reaction of N-2,2,2-trifluoroethylisatin ketimines with conjugated dienes, as shown in Scheme 2, and we are the first to do so. First, the conjugated dienes having electron-neutral (endo-3a), electron-withdrawing (endo-3b–endo-3d and endo-3g) or electron-donating (endo-3e and endo-3f) functional groups on the phenyl ring reacted with 1a to generate the desired products endo-3 with up to >20 : 1 diastereoselectivity in 43–66% yields (Scheme 2, endo-3a–endo-3g). Then various N-2,2,2-trifluoroethylisatin ketimines 1, including 5-Me, 5-Cl, 5-Br, 6-Cl, 7-Me, and 5,7-Me₂, were examined, providing the corresponding spiro[indoline-3,2′-pyrrolidin]-2-ones 3 in 47–96% yields with >20 : 1 diastereoselectivities (Scheme 2, endo-3h–endo-3m). The conjugated dienes bearing different ester groups reacted smoothly with 1a, giving the corresponding products endo-3 in 64%–71% yields (Scheme 2, endo-3n–endo-3p), but low diastereoselectivities were obtained when R³ = R⁴ = Et and Bn (Scheme 2, endo-3n and endo-3o). Finally, various N-protection groups were accommodated, leading to good yields and diastereoselectivities (Scheme 2, endo-3q and endo-3r). Interestingly, when N-Ac of 1 was used, the deprotection product endo-3q was obtained in 97% yield (Scheme 2, endo-3q). Furthermore, the relative configuration of endo-3a was determined by X-ray crystallographic analysis of a single crystal of the pure sample.¹⁴

Scheme 2 Reaction scope in the presence of PCy₃. Reaction conditions: unless otherwise noted, the reactions were conducted with 1 (0.15 mmol) and 2 (0.23 mmol) in 2.0 mL of CH₃CN for 60 h. Isolated yield, dr > 20 : 1; the two isomers could be isolated by flash column chromatography.

We then set out to explore the substrate scope in the presence of K₂CO₃, as shown in Scheme 3. Under the optimized reaction conditions, various N-protection groups (Me, allyl, Ac, and Bn) on N1 of N-2,2,2-trifluoroethylisatin ketimines 1 were examined, leading to good yields and diastereoselectivities (Scheme 3, exo′-4a–exo′-4e). Curiously, the deprotection product exo′-4c was obtained in 59% yield in the presence of N-Ac protection (Scheme 3, exo′-4c). Substrates 2 bearing different ester groups were all tolerated in this transformation, affording their respective products exo′-4f–exo′-4k in moderate to high yields with excellent diastereoselectivities (Scheme 3, exo′-4f–exo′-4k). Besides, the reaction showed good tolerance towards the electronic properties of aromatic substituents; the R² substituent groups of conjugated dienes with electron-withdrawing or electron-donating groups worked well, giving the desired products exo′-4l–exo′-4t in moderate to high yields with excellent diastereoselectivities (Scheme 3, exo′-4l–exo′-4t). A substrate bearing a strong electron-withdrawing group (2,6-Cl₂) formed the product exo′-4u with excellent diastereoselectivity but with a modest yield (Scheme 3, exo′-4u). To further explore the scope, substituted N-2,2,2-trifluoroethylisatin ketimines 1 (including 5,7-Me₂, 5-Cl, 4-Cl, and 7-Me) were also used, and we were pleased to obtain products exo′-4v–exo′-4x bearing vicinal quaternary stereogenic carbon centers in 46–65% yields with >20 : 1 dr (Scheme 3, exo′-4v–exo′-4x). The relative configuration of exo′-4a was determined by X-ray crystallographic analysis of a single crystal of the pure sample.¹⁵

Scheme 3 Reaction scope in the presence of K₂CO₃. Reaction conditions: unless otherwise noted, the reactions were conducted with 1 (0.15 mmol) and 2 (0.23 mmol) in 2.0 mL of CHCl₃ for 48 h. Isolated yield, dr > 20 : 1; the two isomers could be isolated by flash column chromatography. ^cK₂CO₃ (40 mol%).

In order to demonstrate the practicality of our method, we performed the reaction on a large scale. When N-2,2,2-trifluoroethylisatin ketimine 1a and conjugated diene 2a were used in the presence of PCy₃ under the optimal reaction conditions, the reaction proceeded smoothly to afford the desired adduct endo-3a in 66% yield. When a Brønsted base (K₂CO₃) was used, 64% yield of the product exo′-4a was obtained under the optimal reaction conditions (Scheme 4).

Scheme 4 Large scale preparation.

Based on the above experimental observations and on literature precedents,¹⁶ we propose a plausible mechanism for the reaction, as shown in Scheme 5. When PBu₃ was used as the catalyst, initially, the nucleophilic addition of the phosphine catalyst to conjugated diene 2a afforded zwitterionic intermediate A. The subsequent stereospecific nucleophilic addition of intermediate A to N-2,2,2-trifluoroethylisatin ketimine 1a resulted in the formation of intermediate C, which was detected by HRMS analysis (see the ESI, Fig. S1†). Next, an SN₂ substitution reaction occurred, forming the desired product endo-3a and regenerating the phosphine catalyst. When K₂CO₃ was used as the Brønsted base, intermediate E was the first to be obtained; the Michael addition of intermediate E to conjugated diene 2a then occurred to give intermediate F. Subsequently, the stereospecific ring closure and protonation afforded the corresponding product exo′-4a (Scheme 5).

Scheme 5 Plausible reaction mechanism.

In summary, we have developed unique base-promoted diastereoselective (3 + 2) cycloadditions. A diastereodivergent synthesis of fully disubstituted spiro[indoline-3,2′-pyrrolidin]-2-ones was realized by tuning a Lewis base (PCy₃)/Brønsted base (K₂CO₃). The reaction achieved near perfect diastereodivergence in most cases. Significantly, ESI-MS studies were carried out to present a full picture of the reaction processes, and a plausible reaction mechanism is proposed. Further exploration of this diastereodivergent strategy for the construction of biologically valuable molecules is currently underway in our laboratory and will be reported in due course.

Author contributions

K. Li, Z. Zhang, J. Zhu, and Y. Wang performed the experiments. J. Zhao performed the HRMS analysis. E.-Q. and Zheng conceived and directed the project and wrote the paper. All authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21702189, 21672193, and 21272218), the Key Scientific and Technological Project of Henan Province (202102310004), the China Ministry of Industry and Information Technology (Z135060009002), and Zhengzhou University (JC21253007) of China for financial support of this research.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2057244 and 2050077. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1qo01124c

‡ These authors contributed equally to this work.

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