Enantioselective construction of spiro-1,3-indandiones with three stereocenters via organocatalytic Michael-aldol reaction of 2-arylideneindane-1,3-diones and nitro aldehydes

Abstract

Asymmetric domino reaction between 2-arylideneindane-1,3-dione and nitro aldehyde has been developed for the construction of an enantioenriched spiro-1,3-indandione framework with three stereocenters. In the presence of a squaramide-tertiary amine, chiral spiro-1,3-indandione derivatives are obtained in good yields with high enantioselectivities and diastereoselectivities.

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The synthesis of multi-substituted spiro-1,3-indandiones has aroused considerable interest because of their abundance in many natural products with useful biological activities,¹ such as antitumor, antibiotic,² and antiproliferative activity on HL60 and apoptosis resistant leukemia cell lines.³ Among various reported methodologies for accessing the spiro-1,3-indandione skeletons,⁴ organocatalytic domino reactions using readily accessible 2-arylidene-1,3-indandiones have been demonstrated to be a powerful strategy.^5–7 Although diversified Michael donors have been employed in the organocascade reactions for the construction of enantioenriched spiro-1,3-indandione skeletons, impressive results (more than 90% ee) are limited to the use of an aldehyde as a Michael donor, which was catalyzed by a chiral amine derived organocatalyst.^7i–j The only two exceptions were the primary amine catalyzed asymmetric multicomponent reaction among ynones, aldehydes and indan-1,3-diones^7e and the tertiary amine-thiourea catalyzed asymmetric reaction between 2-arylidene-1,3-indandione and nitroalkane.^7g Therefore, efforts in developing an efficient organocatalytic methodology for the construction of enantioenriched spiro-1,3-indandiones are in high demand.

Both β- and γ-nitro aldehydes are resourceful moieties in synthetically useful building blocks and have been efficiently utilized in the total synthesis of natural products and functional cyclic skeletons.⁸ To the best of our knowledge, no results have been reported on the asymmetric domino reaction between nitro aldehyde and 2-arylidene-1,3-indandione for the construction of chiral spiro-1,3-indandione derivatives. As a continuation of our recent efforts,⁹ herein we disclose the first asymmetric synthesis of chiral multi-substituted spiro-1,3-indandiones from nitro aldehyde and 2-arylidene-1,3-indandione via a Michael-aldol reaction sequence using a squaramide as an organocatalyst (Scheme 1).

Scheme 1 Squaramide catalyzed domino reaction.

We initiated our studies by investigating the reaction of 2-benzylidene-1,3-indandione (1a) with 4-nitrobutanal (2a) in CH₂Cl₂ at room temperature in the presence of hydrogen-bonding organocatalysts.¹⁰ The results are shown in Table 1. To our gratification, in the presence of 10 mol% quinidine-based thiourea I,¹¹ the Michael-aldol reaction between 1a and 2a proceeded smoothly and the desired product 3aa was obtained as a single diastereomer (>20 : 1 dr) in 75% yield with 55% ee (Table 1, entry 1). Then some representative bifunctional hydrogen-bonding donor catalysts II–VI were examined in this domino reaction (Table 1, entries 2–6). The results revealed that a squaramide-tertiary amine is more suitable for this asymmetric domino transformation.¹² In particular, 84% yield with 88% ee and >20 : 1 dr could be obtained when squaramide VI derived from quinidine was employed as an organocatalyst (Table 1, entry 6). To achieve high yield and asymmetric induction, further optimization of reaction conditions was carried out. After screening of common solvents, it was found that reaction media only affected the yield obviously and had less effect on the asymmetric induction (Table 1, entries 7–10). The best yield, 84%, was obtained when the domino reaction was carried out in CH₂Cl₂ (Table 1, entry 6). Subsequent investigations on the additive indicated that molecular sieves could increase the ee value slightly (Table 1, entries 11 and 12). Under optimized reaction conditions, enantioenriched spiro-1,3-indandione 3aa was obtained in 83% yield with 90% ee and >20 : 1 dr (Table 1, entry 12). Importantly, lowering catalyst loading from 10 mol% to 5 mol% led to a similar yield without compromising enantioselectivity and diastereoselectivity (Table 1, entry 13).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Yield^b (%)	ee^c (%)	dr^c
a Reaction conditions: a mixture of 1a (0.2 mmol), catalyst (10 mol%), and 2a (0.24 mmol) in solvent (2.0 mL) was stirred at room temperature for 12 h. b Isolated yield. c Determined by chiral HPLC analysis. d 4 Å MS (30 mg) was added. e 5 Å MS (30 mg) was added. f Catalyst (5 mol%) was used.
1	I	CH2Cl2	75	55	>20 : 1
2	II	CH2Cl2	60	41	>20 : 1
3	III	CH2Cl2	76	27	>20 : 1
4	IV	CH2Cl2	75	3	>20 : 1
5	V	CH2Cl2	78	−82	>20 : 1
6	VI	CH2Cl2	84	88	>20 : 1
7	VI	Toluene	76	88	>20 : 1
8	VI	THF	72	88	>20 : 1
9	VI	EtOAc	50	84	>20 : 1
10	VI	Et2O	52	88	>20 : 1
11^d	VI	CH2Cl2	85	89	>20 : 1
12^e	VI	CH2Cl2	83	90	>20 : 1
13^f	VI	CH2Cl2	80	90	>20 : 1

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With optimum reaction conditions in hand, the scope of the Michael-aldol domino reactions between various 2-arylidene-1,3-indandiones (1) and 4-nitrobutanal (2a) was investigated, and the results are summarized in Table 2.

Table 2 Scope of the Michael-aldol reaction between 1 and 2a^a

a A mixture of 1 (0.2 mmol), 5 Å MS (30 mg), VI (10 mol%), and 2a (0.24 mmol) in CH₂Cl₂ (2.0 mL) was stirred at room temperature for 12 h. And products 3 were obtained in isolated yield. Both enantioselectivities and diastereoselectivities were determined by chiral HPLC analysis.

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A set of 2-arylidene-1,3-indandiones (1a–i) with different substitution patterns with respect to electronic properties, steric hindrance, and substitution positions on the aromatic ring were surveyed to react with 4-nitrobutanal (2a) and the desired enantioenriched spiro-1,3-indandiones (Table 2, 3aa–ia) were obtained as single diastereomers (>20 : 1 dr) in good yields (68–83%) with moderate to good enantioselectivities (66–90% ee). No significant electron effect on the aromatic moiety was observed. The position of the substituents on the aromatic ring had a little influence on the enantioselectivity. Both 2-(4-substituted-arylidene)-1,3-indandiones (1b–e) and 2-(2-substituted-arylidene)-1,3-indandiones (1h, 1i) afforded chiral spiro-1,3-indandiones (Table 2, 3ba–ea, 3ha, 3ia) with moderate to good enantioselectivities (66–90% ee). Comparatively, 2-(3-substituted-arylidene)-1,3-indandiones (1f, 1g) furnished spiro-products with moderate enantioselectivities (Table 2, 3fa, 3ga). To explore the scope of the domino reaction, heteroaromatic 1,3-indandiones were also investigated. The reaction between 2-((furan-2-yl)methylene)-2H-indene-1,3-dione (1j) and 2a proceeded smoothly to afford the corresponding spiro-product in 84% yield with 88% ee and 97.8 : 2.2 dr (Table 2, 3ja). And 2-((thiophen-2-yl)methylene)-2H-indene-1,3-dione (1k) was found to react with 2a slowly to afford the corresponding product in 61% yield with 74% ee and >20 : 1 dr (Table 2, 3ka).

To further explore the scope of the domino reaction, the VI-mediated Michael-aldol reactions between a series of 2-arylidene-1,3-indandiones (1) and 3-nitropropanal (2b) were then probed as shown in Table 3. Under the same optimized conditions, enantioenriched spiro-1,3-indandione-cyclopentanol 3ab was obtained in 94% yield with 90% ee and >20 : 1 dr from the domino reaction between 1a and 2b (Table 3, 3ab). Both electron-withdrawing (Table 3, 3bb, 3fb, 3gb) and electron-donating groups (Table 3, 3db), could be introduced into the aromatic ring of 2-arylidene-1,3-indandione, respectively. And 2-(4-substituted-arylidene)-1,3-indandiones furnished the desired products with higher enantioselectivities than those of the corresponding products from 2-(3-substituted-arylidene)-1,3-indandiones. This is in agreement with the results obtained from the domino reactions between 1a and 2a.

Table 3 Scope of the Michael-aldol reaction between 1 and 2b^a

a A mixture of 1 (0.2 mmol), 5 Å MS (30 mg), VI (10 mol%), and 2b (0.24 mmol) in CH₂Cl₂ (2.0 mL) was stirred at room temperature for 72 h. And products 3 were obtained in isolated yield. Both enantioselectivities and diastereoselectivities were determined by chiral HPLC analysis.

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The absolute configuration of adduct 3ea, based on the VI-catalyzed Michael-aldol reaction, was unambiguously determined by single-crystal X-ray crystallography (Fig. 1).¹³ As shown in Fig. 1, the absolute configuration of C6, C15 and C18 in the structure of 3ea was R-configuration. The stereochemistry of other products was assigned by analogy.

Fig. 1 X-ray crystal structure of product 3ea.

Conclusions

In summary, we have developed a highly efficient asymmetric organocatalytic Michael-aldol domino reaction for the construction of a functionalized enantioenriched spiro-indane-1,3-dione skeleton. In the presence of the available squaramide organocatalyst, various 2-arylidene-1,3-indandiones reacted with 4-nitrobutanal and 3-nitropropanal smoothly to furnish the desired chiral spiro-1,3-indandiones in moderate to high yields with good to high diastereoselectivities and enantiocontrol. Importantly, the spiro ring system containing three stereocenters could be built in one pot via this methodology in a high asymmetric level. Further investigations involving the application of this catalytic approach are currently underway in our laboratory.

Acknowledgements

We gratefully acknowledge the start-up fund from the South University of Science and Technology of China (SUSTC) and the National Natural Science Foundation of China (NSFC 21302089) for financial support.

Notes and references

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13. CCDC 1402191.

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Footnotes

† Dedicated to Professor Zongshi Li on the occasion of his 80th birthday.

‡ Electronic supplementary information (ESI) available. CCDC 1402191. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00166h

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