Organocatalytic tandem enantioselective Michael-cyclization of isatin-derived β,γ-unsaturated α-ketoesters with 3-hydroxy-4H-chromen-4-one or 2-hydroxy-1,4-naphthoquinone derivatives

Abstract

The enantioselective formal [3 + 3] annulation reaction of isatin-derived β,γ-unsaturated α-ketoesters with 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinone was successfully implemented under catalysis of quinine-derived bifunctional tertiary amine-thiourea catalysts. The efficient tandem Michael-cyclization has provided facile access to optically active spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives in high yields with excellent diastereo- and enantioselectivities.

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The design and synthesis of structurally distinct enantio-enriched organic spiro-oxindole carbocyclic¹ and spiro-oxindole heterocyclic compounds² have always been attractive and dynamic research areas because of the considerable appearance of these compounds in natural products and synthetic molecules. Thus, the development of an efficient methodology for the construction of spiro[oxindole-heterocycle] compounds is enthusiastically targeted by synthetic chemists. So far, a number of synthetic methods have been developed in pursuit of these types of diversely functionalized spirocyclic oxindoles, including intermolecular alkylation,³ cycloadditions,⁴ sigmatropic rearangements,⁵ and others, which were successfully performed by transition metal catalysis⁶ or organocatalytic tandem strategies.⁷

Recently, there has been much interest in the application of β,γ-unsaturated α-ketoesters⁸ as synthons due to the unique reaction sites of the electron-deficient β,γ-unsaturated system and the activated α-ketone group. However, isatin-derived β,γ-unsaturated α-ketoesters, as a type of versatile and practical molecular backbone, have seldom been applied in organic transformations.⁹ In 2014, by using a (DHQ)₂AQN as the organocatalyst, Shi and co-workers reported the first asymmetric domino annulation reaction of isatin-derived β,γ-unsaturated α-ketoesters with allenoates to yield the corresponding spirooxindole heterocycle products in good to excellent catalytic outcomes.^9a Very recently, Kesavan and co-workers reported an asymmetric tandem Michael-cyclization with isatin-derived β,γ-unsaturated α-ketoesters and pyranopyrazoles under the catalysis of a chiral bifunctional squaramide derived from L-proline.^9c

In the literature, chromen-4-one¹⁰ and naphthoquinone¹¹ structural motifs have been reported to be highly versatile building blocks for the construction of various heterocycle compounds (Scheme 1). Furthermore, chromen-4-one and naphthoquinone derivatives are found in many natural products and pharmaceuticals with a wide range of physiological and biological activities such as anti-bacterial,¹² anti-fungal,¹³ anti-cancer¹⁴ anti-diabetes¹⁵ and anti-HIV¹⁶ activities. Previously, we reported the organocatalytic asymmetric cascade Michael-cyclization reaction of 2-hydroxynaphthalene-1,4-diones to isatylidene malononitriles, which provided the desired spiro[4H-benzo[g]chromene-indoline] derivatives in excellent catalytic outcomes.^17,18 During our preparation of this manuscript, Kesavan and co-workers reported similar cascade reactions using isatin-derived β,γ-unsaturated α-ketoesters and 2-hydroxy-1,4-naphthoquinone as the substrates via an L-proline derived bifunctional squaramide as the catalyst.¹⁹ Herein, we report our preliminary catalytic results on the enantioselective formal [3 + 3] annulation reaction between isatin-derived β,γ-unsaturated α-ketoesters and 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinones, which were respectively catalyzed by quinine-derived bifunctional tertiary amine-thiourea catalysts. Two types of enantiomerically enriched spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives were obtained in high yields with excellent diastereo- and enantioselectivities (Scheme 2).

Scheme 1 Some natural products and pharmaceuticals with structural cores of chromen-4-ones and naphthoquinones.

Scheme 2 Screening of organocatalysts.

Initially, we started to investigate the tandem Michael-cyclization reaction of ethyl 3-hydroxy-4H-chromen-4-one (2a) and ethyl (E)-3-(1-methyl-2-oxoindolin-3-ylidene)-2-oxopropanoate (3a) by using 10 mol% of an isosteviol derived bifunctional thiourea (1a) as the catalyst in toluene at room temperature. It was found that the cascade process proceeded smoothly to furnish the desired spiro[oxindole-pyrano[3,2-b]chromenone] 4a in an 89% yield, >20 : 1 diastereomeric ratio (dr) and 63% enantiomeric excess (ee) (Table 1, entry 1). When the (1R,2R)-1,2-cyclohexanediamine (CHDA) and (1R,2R)-1,2-diphenylethane-1,2-diamine (DPEN) derived bifunctional thiourea catalysts 1b and 1c were employed in this reaction, the desired product 4a was afforded in 77% and 46% yields with 59% and 65% ee, respectively (Table 1, entries 2 and 3). Encouraged by these promising results, we next examined a series of bifunctional H-bond donor catalysts, including the chiral squaramides 1d and 1e and bifunctional tertiary amine-thioureas 1f–1i derived from different privileged chiral scaffolds. The catalytic results showed that the catalysts probed displayed different catalytic reactivity and enantioselectivity toward the tandem Michael-cyclization reaction (Table 1, entries 4–11). Among them, the catalyst 1i, a chiral quinine-derived bifunctional tertiary amine-thiourea catalyst, was proven to be efficient for this transformation, which provided the desired product 4a in a 77% yield, >20 : 1 dr, and 80% ee (Table 1, entry 9).

Table 1 Optimization of organocatalysts for the tandem Michael-cyclization reaction

Entry^a	Cat.	Time (h)	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise indicated, the reaction was conducted with 2a (0.1 mmol), 3a (0.1 mmol) and cat. 1 (10 mol%) in toluene (1 mL) at room temperature.b Isolated yield.c Determined by proton nuclear magnetic resonance spectroscopy (^1H NMR).d Determined by chiral high performance liquid chromatography (HPLC) analysis using a Chiralpak IA-H.e Ent-4a was obtained.
1	1a	12	89	>20 : 1	63
2	1b	12	77	>20 : 1	59^e
3	1c	12	46	>20 : 1	65^e
4	1d	12	95	>20 : 1	39
5	1e	12	Trace	>20 : 1	ND
6	1f	12	77	>20 : 1	73^e
7	1g	12	76	>20 : 1	67
8	1h	12	77	>20 : 1	56
9	1i	12	77	>20 : 1	80

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To further optimize the reaction conditions, some other reaction parameters, including reaction medium, substrate ratio, substrate concentration and reaction temperature, were examined in the presence of 10 mol% of the catalyst 1i, and the results are shown in Table 2. Firstly, some common solvents such as tetrahydrofuran (THF), mesitylene, p-xylene, Et₂O, CH₂Cl₂, DCE, CH₃CN, CHCl₃, and CCl₄ were tested, and it was observed that CH₂Cl₂ was the optimal reaction medium. The corresponding reaction gave the desired product 4a in an 87% yield with >20 : 1 dr, 87% ee (Table 2, entry 5). Subsequently, the reaction substrate ratio was tested. It was disclosed that 1.5 to 1.0 of 2a to 3a was the optimal ratio and the corresponding reaction gave the desired products in a 95% yield with >20 : 1 dr, 89% ee (Table 2, entry 13 vs. entries 10–12).

Table 2 Optimization of the reaction conditions

Entry^a	Solvent	Time (h)	Conc. (mol L^−1)	Temp. (°C)	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise indicated, the reaction was conducted with 2a (0.1 mmol), 3a (0.1 mmol) and cat. 1i (10 mol%) in solvent (1 mL) at room temperature for 12 hours.b Isolated yield.c Determined by ^1H NMR.d Determined by chiral HPLC analysis using a Chiralpak IA-H.e 2a (0.1 mmol) and 3a (0.12 mmol) were used.f 2a (0.1 mmol) and 3a (0.15 mmol) were used.g 2a (0.12 mmol) and 3a (0.1 mmol) were used.h 2a (0.15 mmol) and 3a (0.1 mmol) were used.i cat. 1i (5 mol%) was used.j cat. 1i (2.5 mol%) was used.
1	THF	12	0.1	25	65	>20 : 1	45
2	Mesitylene	12	0.1	25	79	>20 : 1	77
3	p-Xylene	12	0.1	25	74	>20 : 1	80
4	Et2O	12	0.1	25	80	>20 : 1	74
5	DCM	12	0.1	25	87	>20 : 1	87
6	DCE	12	0.1	25	94	>20 : 1	82
7	CH3CN	12	0.1	25	73	>20 : 1	80
8	CHCl3	12	0.1	25	92	>20 : 1	84
9	CCl4	12	0.1	25	90	>20 : 1	86
10^e	DCM	12	0.1	25	81	>20 : 1	86
11^f	DCM	12	0.1	25	84	>20 : 1	86
12^g	DCM	12	0.1	25	95	>20 : 1	88
13^h	DCM	12	0.1	25	95	>20 : 1	89
14^h	DCM	12	0.2	25	96	>20 : 1	88
15^h	DCM	12	0.4	25	93	>20 : 1	89
16^h	DCM	12	0.06	25	93	>20 : 1	88
17^h	DCM	12	0.05	25	98	>20 : 1	88
18^h	DCM	12	0.1	0	79	>20 : 1	96
19^h	DCM	12	0.1	−10	75	>20 : 1	97
20^h	DCM	24	0.1	−20	99	>20 : 1	98
21^h^,^i	DCM	24	0.1	−20	86	>20 : 1	98
22^h^,^j	DCM	24	0.1	−20	72	>20 : 1	98
23^h^,^i	DCM	40	0.1	−20	97	>20 : 1	98

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Meanwhile, when the reaction concentration fluctuated, we found that there was no significant influence on the reactivity and enantioselectivity (Table 2, entries 14–17). In addition, when the reaction temperature was lowered from room temperature (rt) to 0 °C, the desired product was obtained in a 79% yield, >20 : 1 dr, and 96% ee (Table 2, entry 18). Finally, after further examination of the reaction temperature and the catalyst loading, the optimized reaction conditions were established as follows: 1.5 to 1.0 of 2a to 3a of substrate molar ratios with a substrate concentration of 0.1 M in the presence of 5.0 mol% catalyst 1i in dichloromethane (DCM) at −20 °C (Table 2, entry 23).

Having established the optimal reaction conditions, we then moved to the study of the scope and limitations of the tandem Michael-cyclization reaction of the isatin-derived β,γ-unsaturated α-ketoesters 3a–3s with 3-hydroxy-4H-chromen-4-one 2a, as shown in Table 3. On the one hand, the effects of the N-protecting groups of R¹ on the oxindolyl motifs were firstly evaluated for this transformation. For the substrates 3b–3d bearing the N-protecting groups of electron-donating substituents (–MOM, –Bn and –Allylic), the corresponding reactions were performed well and the desired products 4b–4d were achieved in high yields, with over 20 : 1 dr and excellent enantioselectivities, respectively (Table 3, entries 2–4). In contrast, when the N-protecting groups were on electron-withdrawing substituents (–Cbz, and –Ac), the corresponding desired products 4e and 4f were respectively obtained in moderate yields, >20 : 1 dr, albeit with good enantioselectivities (Table 3, entries 5 and 6). On the other hand, we discovered that the substrates 3 with different substituents (–F, –Cl, –Br, –Me, and –OMe) could smoothly participate in the tandem Michael-cyclization reaction, which provided the desired products 4g–4r in 74–99% yields, >20 : 1 dr, and 93–>99% ees. Apparently, both electron-withdrawing substituents (–F, –Cl, or –Br) and electron-donating substituents (–Me or –OMe) at the 5- or 7-positions on the oxindolyl motifs in 3g–3k, 3o and 3p were well tolerated, and the desired products 4g–4k, 4o and 4p were furnished in 77–99% yields with 93–99% ees, respectively (Table 3, entries 7–11 and entries 15–16). Meanwhile, for the substrates 3l–3n bearing the substituents –Cl, –Br, –OMe on the 6-positions of the oxindolyl motifs, the corresponding reactions generally exhibited inferior reactivity, although the desired products 4l–4n were respectively produced in 74–86% yields with 97–>99% ees (Table 3, entries 12–14). Furthermore, the substrates 3q and 3r with 5,7-dimethyl or 5,6-difloro groups were also well tolerated, and the desired products 4q and 4r were obtained in 80% and 96% yields with 98% and 93% ees, respectively (Table 3, entries 17 and 18). Finally, we observed that a methoxycarbonyl group in substrate 3s has no effect on its catalytic outcomes compared with the ethoxycarbonyl group in 3a (Table 3, entry 19 vs. entry 1).

Table 3 Substrate scope of the isatin-derived β,γ-unsaturated α-ketoesters 3a–3s

Entry^a	3	R^1	R^2	R^3	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise indicated, the reaction was conducted with 2a (0.15 mmol), 3 (0.1 mmol) and cat. 1i (5 mol%) in DCM (1 mL) at −20 °C for 40 hours.b Isolated yield.c Determined by ^1H NMR.d Determined by chiral HPLC analysis.
1	3a	CH3	H	Et	97/4a	>20 : 1	98
2	3b	MOM	H	Et	95/4b	>20 : 1	98
3	3c	Bn	H	Et	98/4c	>20 : 1	99
4	3d	Allylic	H	Et	97/4d	>20 : 1	99
5	3e	Cbz	H	Et	73/4e	>20 : 1	99
6	3f	Ac	H	Et	54/4f	>20 : 1	98
7	3g	CH3	5-F	Et	82/4g	>20 : 1	98
8	3h	CH3	5-Cl	Et	77/4h	>20 : 1	94
9	3i	CH3	5-Br	Et	89/4i	>20 : 1	93
10	3j	CH3	5-Me	Et	99/4j	>20 : 1	96
11	3k	CH3	5-OMe	Et	98/4k	>20 : 1	98
12	3l	CH3	6-Cl	Et	86/4l	>20 : 1	97
13	3m	CH3	6-Br	Et	86/4m	>20 : 1	97
14	3n	CH3	6-OMe	Et	74/4n	>20 : 1	>99
15	3o	CH3	7-F	Et	99/4o	>20 : 1	99
16	3p	CH3	7-Me	Et	99/4p	>20 : 1	>99
17	3q	CH3	5,7-2Me	Et	80/4q	>20 : 1	98
18	3r	CH3	5,6-2F	Et	96/4r	>20 : 1	93
19	3s	CH3	H	Me	98/4s	>20 : 1	98

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Under otherwise identical reaction conditions, the structural variations of the substrates 2 were also explored, and the catalytic results are summarized in Table 4. 3-Hydroxy-4H-chromen-4-ones 2a–2e bearing both electron-donating and electron-withdrawing substituents on the phenyl groups were all tolerated, and the corresponding reactions proceeded smoothly to afford the desired products 4t–4w in 65–99% yields with 92–99% ees, respectively (Table 4, entries 1–5). For 3-hydroxy-4H-chromen-4-ones 2b–2d bearing substituents (–F, –Br, or –Me) at the 6-positions of the phenyl rings, their electronic and steric properties had some influence on the yields of the corresponding reactions and no significant effect on their enantioselectivities (Table 4, entries 2–4). For the substrate 2e bearing a –OMe substituent at the 7-position of the phenyl ring, the tandem Michael-cyclization reaction proceeded well to furnish the desired product 4w in a 99% yield, >20 : 1 dr and 99% ee (Table 4, entry 5). Single crystals of rac-4u were obtained from ethyl acetate and n-hexane, and the relative configurations of the chiral stereo centers of the hemiketal and the spiro quaternary carbon were unambiguously determined by X-ray diffraction analysis (Scheme 3).

Table 4 Substrate scope on 3-hydroxy-4H-chromen-4-ones 2a–2e

Entry^a	2	R	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise indicated, the reaction was conducted with 2 (0.15 mmol), 3a (0.1 mmol) and cat. 1i (5 mol%) in DCM (1 mL) at −20 °C for 40 hours.b Isolated yield.c Determined by ^1H NMR.d Determined by chiral HPLC analysis.
1	2a	H	97/4a	>20 : 1	98
2	2b	6-F	88/4t	>20 : 1	93
3	2c	6-Br	65/4u	>20 : 1	92
4	2d	6-Me	97/4v	>20 : 1	98
5	2e	7-OMe	99/4w	>20 : 1	99

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Scheme 3 Single-crystal X-ray crystallography of rac-4u.²⁰

The tandem Michael-cyclization process then extended to various isatin-derived β,γ-unsaturated α-ketoesters with 2-hydroxy-1,4-naphthoquinones 5 as a nucleophile, which can furnish optically active spiro[oxindole-benzo[g]chromene-dione] derivatives. By using the optimized reaction conditions (the optimization reaction is detailed in the ESI†), we proceeded to explore the substrate scope of the reaction, as shown in Table 5. The effect of the N-protecting groups of 3 was firstly evaluated. N-protecting groups on substrates 3 could be both electron-donating groups (–MOM, –Bn and –Allylic) and electron-withdrawing groups (–Cbz, and –Ac), and all the reactions proceeded smoothly and provided the desired products 6b–6g in good yields with excellent enantioselectivities, respectively (Table 5, entries 2–6). Meanwhile, when the substrates 3g–3k with different substituents (–F, –Cl, –Br, –Me, –OMe) on the 5-positions of the oxindolyl backbones were employed in the tandem Michael-cyclization reaction, the desired products 6g–6k were respectively furnished in 70–92% yields, >20 : 1 dr, and 97% ees (Table 5, entries 7–11). The substrates 3l–3n bearing –Cl, –Br, –OMe substituents at the 6-positions of the oxindolyl motifs led to their desired products 6l–6n in 55–69% yields, >20 : 1 dr, albeit all with 97% ees (Table 5, entries 12–14). Further exploration of substrate scope revealed that the reactions of 3o and 3p, which contain a fluoro or a methyl group at the 7-positions on the oxindolyl motifs, also proceeded well and afforded the corresponding products 6o and 6p in 61% and 70% yields with 93% and 98% ees, respectively (Table 5, entries 15 and 16). Furthermore, the substrates 3q and 3r with 5,7-dimethyl or 5,6-difluoro groups were also well tolerated and the desired products 6u and 6v were obtained in 70% and 78% yields with 94% and 95% ees, respectively (Table 5, entries 17 and 19). In addition, substrate 3s with a methoxycarbonyl group and 2-hydroxy-7-methylnaphthalene-1,4-dione acting as a nucleophile have also been introduced into this transformation, the corresponding tandem Michael-cyclization reactions have been successfully implemented and resulted in the desired products 6s and 6t in good catalytic outcomes, respectively (Table 5, entries 19 and 20).

Table 5 Substrate scope on the tandem Michael-cyclization reaction

Entry^a	3	R^1	R^2	R^3	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise indicated, the reaction was conducted with 5 (0.12 mmol), 3 (0.1 mmol) and cat. 1h (5 mol%) in DCM (0.5 mL) at room temperature for 12 hours.b Isolated yield.c Determined by ^1H NMR.d Determined by chiral HPLC analysis.e 10 mol% cat. 1h was added.f The reaction was carried out for 36 h.g 2-Hydroxy-7-methylnaphthalene-1,4-dione was used as the nucleophile.
1	3a	CH3	H	Et	81/6a	>20 : 1	98
2	3b	MOM	H	Et	67/6b	>20 : 1	97
3	3c	Bn	H	Et	52/6c	>20 : 1	97
4	3d	Allylic	H	Et	70/6d	>20 : 1	96
5	3e	Cbz	H	Et	59/6e	>20 : 1	97
6^e	3f	Ac	H	Et	56/6f	>20 : 1	97
7^f	3g	CH3	5-F	Et	70/6g	>20 : 1	97
8	3h	CH3	5-Cl	Et	88/6h	>20 : 1	97
9	3i	CH3	5-Br	Et	92/6i	>20 : 1	97
10	3j	CH3	5-Me	Et	87/6j	>20 : 1	97
11	3k	CH3	5-OMe	Et	72/6k	>20 : 1	97
12	3l	CH3	6-Cl	Et	69/6l	>20 : 1	97
13	3m	CH3	6-Br	Et	55/6m	>20 : 1	97
14	3n	CH3	6-OMe	Et	63/6n	>20 : 1	97
15	3o	CH3	7-F	Et	61/6o	>20 : 1	93
16^e	3p	CH3	7-Me	Et	70/6p	>20 : 1	98
17	3q	CH3	5,7-2Me	Et	70/6q	>20 : 1	94
18	3r	CH3	5,6-2F	Et	78/6r	>20 : 1	95
19	3s	CH3	H	Me	74/6s	>20 : 1	>99
20^g	3a	CH3	H	Et	85/6t	>20 : 1	93

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To demonstrate the potential utility of this methodology, a gram-scale synthesis of 4w was carried out in the presence of a 1.0 mol% catalyst loading, which afforded 1.45 grams of 4w in 92% yield with >20 : 1 dr and 98% ee (Scheme 4). Then, the compound 4w reacted with trimethylsilyl chloride (TMSCl) in the presence of triethylamine in order to protect the hemiketal –OH group with trimethlysilyl (TMS), and the resulting chlorinated product 7 was produced in a 52% yield with a little erosion of the enantiomeric purity. Furthermore, in consideration of the instability of the resulting hemiketals 6, treating the product 6a of the tandem Michael-cyclization reaction with mesyl chloride in the presence of triethylamine, we found that the optically active methanesulfonate 8 was formed in a 92% yield, 8 : 1 dr and 94% ee (Scheme 4).

Scheme 4 Further investigation of the potential of the reaction.

Conclusions

In summary, we have demonstrated a highly efficient tandem Michael-cyclization reaction between isatin-derived β,γ-unsaturated α-ketoesters and 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinone, which were respectively catalyzed by quinine-derived bifunctional tertiary amine-thiourea catalysts. Two types of enantiomerically enriched spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives, bearing a spiro quaternary and hemiketal stereogenic center, were obtained in good yields with excellent diastereoselectivities and enantioselectivities. Further efforts will be focused on the development of a more efficient tandem cyclization process and the application of these diverse enantio-enriched compounds.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (21272166, 21572150), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (13KJA150004), the Program for New Century Excellent Talents in University (NCET-12-0743), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The authors also thank Professor Hongchao Guo for providing several chiral compounds (synthesized in the National Key Technologies R&D Program of China, 2015BAK45B01, CAU).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1446846. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra17400k

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