Asymmetric synthesis of poly-substituted spirocyclohexane oxindole via a squaramide catalyzed cascade Michael–Michael–aldol sequence

Abstract

A squaramide-catalyzed Michael–Michael–aldol cascade sequence of three readily accessible substrates (1,3-dicarbonyl compound, nitroalkene and methyleneindolinone) was developed. The reactions led to a series of enantioenriched spirocyclohexane oxindoles bearing six contiguous stereocenters in good yields (up to 85%) and with excellent stereoselectivities (>20 : 1 dr, >99% ee).

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Introduction

The prevalence of spirocyclic oxindole architecture in a variety of natural products and synthetic bioactive compounds has underlined the importance of general asymmetric methods for their efficient construction.¹ In particular, spirocyclohexane oxindoles have intrigued the chemistry community for years, with a unique synthetic challenge. Significant efforts have been made for the stereoselective construction of the requisite all-carbon spiroquaternary and other multiple stereocenters for such complex structures.² Recently, a number of elegant asymmetric assemblies of spirocyclohexane oxindoles^3,4 were accomplished by means of organocatalytic domino reactions,⁵ in which small organic molecules are used to mediate multiple chemical transformations in a consecutive and protecting group free fashion. The reactions are conducted under mild conditions with remarkable step, atom and redox economy. Notably, these established methods are mainly based on chiral amine catalyzed syntheses through cascade reactions³ or Diels–Alder reactions.⁴ Nevertheless, to the best of our knowledge, the asymmetric synthesis of spirocyclohexane oxindoles bearing six contiguous stereocenters is rare to date. Steric hindrance arising from the multiple crowded groups of cyclohexane, in combination with the difficulties in constructing the all-carbon spiroquaternary stereocenter with an excellent stereocontrol, presents an extremely hard task to design highly stereoselective approaches towards fully substituted spirocyclohexane oxindoles. Therefore, new strategies for the efficient and stereospecific synthesis of fully substituted spirocyclohexane oxindoles from readily available starting materials are still in great demand.

Previously, we reported several organocatalyzed cascade reactions for the asymmetric preparation of densely substituted six-membered rings bearing contiguous stereocenters using easily accessible starting materials.⁶ Inspired and encouraged by these results, we reasoned that 1,3-dicarbonyl compounds 1 not only could undergo Michael addition with both nitroalkenes 2 and methyleneindolinones 3 but also could serve as electrophiles for an intramolecular aldol or Henry reaction. The conjugated additions of dicarbonyl compounds to nitroalkenes or oxindoles catalyzed by bifunctional catalysts have been well studied.⁷ As such, these Michael adducts (I, II) would attack another Michael acceptor under identical conditions in the following step. Consequently, two types of multifunctional spirocyclic oxindoles (4, 5) would be generated from these simple substrates through a cascade reaction (Scheme 1). We herein disclose an organocatalytic cascade Michael/Michael/aldol sequence for the construction of spirocyclohexane oxindole bearing six adjacent stereocenters in a highly efficient and stereospecific manner using β-dicarbonyl compound, nitroalkene and methyleneindolinone under mild conditions. It is worth noting that Enders and co-workers reported the synthesis of spiropyrazolones using a similar strategy while this manuscript was in preparation.⁸

Scheme 1 Asymmetric organocatalytic cascade strategy for the privileged six-membered rings.

Results and discussion

Initially, the cascade Michael–Michael–aldol sequence was set up in a one-pot fashion using acetylacetone 1a, nitroalkene 2a and unprotected methyleneindolinone 3a in DCM at room temperature with 5 mol% of a chiral squaramide as the catalyst. Unfortunately, no desired spirocyclohexane oxindole was obtained but the Michael adduct of 1,3-diketone and nitroalkene was isolated in nearly quantitative yield after 24 hours (Table 1, entry 1). Then, different protecting groups on the N atom of methyleneindolinone were tested. N-Methyl and N-benzyl protected substrates showed less reactivity in this cascade reaction (Table 1, entries 2, 3). N-Acetyl methyleneindolinone furnished the desired product in 15% yield with 1 : 1 dr and >99% ee (Table 1, entry 4). To our delight, when N-Boc protected methyleneindolinone was examined, the desired product 4a was obtained in 25% yield with >20 : 1 dr and >99% ee. However the chemoselectivity (4a : 5a = 1 : 2.5) and the diastereoselectivity of 5a (2.5 : 1) were very low (Table 1, entry 5). To improve the yield and selectivities, the cascade reaction was performed in a stepwise-fashion by adding N-Boc-protected methyleneindolinone after nitroalkene was consumed completely.⁹ Gratifyingly, a much higher yield (85%) of 4a was achieved, along with excellent stereoselectivity (>20 : 1 dr, >99% ee) and chemoselectivity (4a : 5a >20 : 1) (Table 1, entry 6). Other solvents, such as CHCl₃, CCl₄, THF and toluene, gave slightly lower yields compared to DCM (Table 1, entries 7–10). Taken together, the proposed cascade reaction could be realized by adding N-Boc-protected methyleneindolinone after the first Michael addition was completed in the presence of 5 mol% Q-6 in DCM at room temperature. (For the reaction of isolated Michael addition adducts with methyleneindolinone catalyzed by achiral base, see ESI†).

Table 1 Optimization of cascade reaction conditions^a

Entry	R	Time (h)	Solvent	Yield^b (%)(4a)	dr^c	ee^c (%)
a The reaction was performed using 0.22 mmol of 1a, 0.2 mmol of 2a, 5 mol% of Q-6, and 0.3 mmol of 3a in solvent (1.0 M) at room temperature. For results of other catalysts and bases, see ESI. b Isolated yield of 4a. c dr was determined by chiral HPLC. d 4a : 5a = 1 : 2.5 (5a, 2.5 : 1 dr, 96% ee). e 3a was added after 2a was consumed completely.
1	H	24	DCM	—	—	—
2	Me	24	DCM	—	—	—
3	Bn	24	DCM	—	—	—
4	Ac	24	DCM	15%	1 : 1	>99%
5^d	Boc	24	DCM	25%	>20 : 1	>99%
6^e	Boc	1 + 21	DCM	85%	>20 : 1	>99%
7^e	Boc	1 + 21	CHCl3	78%	>20 : 1	>99%
8^e	Boc	1 + 30	CCl4	73%	>20 : 1	>99%
9^e	Boc	1 + 21	THF	71%	>20 : 1	>99%
10^e	Boc	1 + 30	Toluene	76%	>20 : 1	>99%

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With the optimized conditions in hand, the substrate scope was explored as summarized in Fig. 1. In general, the reaction could produce the corresponding products in moderate to good yields (up to 85%) and with excellent stereoselectivities (>20 : 1 dr, >99% ee, in all cases). Aryl substituted nitroalkenes bearing either electron-withdrawing or electron-donating groups on the phenyl ring were well tolerated (Fig. 1, 4a–4f), affording the desired compounds in high yields (71–85%). Nitroalkenes with alkyl substitutions, proven to be not good substrates, gave moderate yields but poor selectivities (see ESI† for details). Desirable results (77–87% yields) were obtained when nitroalkenes bearing heteroaromatic rings were employed (Fig. 1, 4g, 4h). Additionally, this cascade reaction was amenable to various N-Boc protected methyleneindolinones, providing the desired products in moderate to good yields (32–79%) (Fig. 1, 4i–4l). It is worth noting that the employment of ethyl acetoacetate (Fig. 1, 4m–4o) and ethyl benzoylacetate (Fig. 1, 4p) also afforded the expected spirocyclic oxindoles with excellent stereoselectivities (>20 : 1 dr, >99% ee). The absolute configuration of the cascade Michael–Michael–aldol reaction product was unambiguously assigned based on the single-crystal X-ray analysis of the N-Boc-deprotected product of 4b (Fig. 2).¹⁰

Fig. 1 Substrate scope.^{a a}Reaction conditions: the reaction was performed using 0.22 mmol of 1, 0.20 mmol of 2, 5 mol% of Q-6 and 0.3 mmol of 3 in DCM (1.0 M) at room temperature. The isolated yield. ^bdr was determined by crude ¹H NMR. ^cThe ee value of the major product was determined by chiral HPLC.

Fig. 2 X-ray structure of the N-Boc-deprotected product of 4b.¹¹

Encouraged by the above results, we next sought to diversify the six-membered spirocyclic oxindoles by reducing the nitro-group or removing the N-Boc-group of the obtained products selectively (Scheme 2). The reactions proceeded smoothly to afford the desired compounds (Scheme 2, 6o, 7o, 8o). Notably, the newly formed amine groups in the products 7o and 8o could serve as a convenient handle for further transformations.

Scheme 2 Transformations of the obtained spirocyclohexane oxindoles.

To further demonstrate the practicality and efficiency of this cascade Michael–Michael–aldol sequence, a gram-scale synthesis of poly-substituted spirocyclohexane oxindole was achieved in 76% yield with excellent stereoselectivity (>20 : 1 dr, >99% ee) (Scheme 3). Although a prolonged reaction time was needed, this result illustrated a very promising outlook for the applicability of this cascade reaction. When a lower catalyst loading (2 mol%) was applied in the gram-scale synthesis, a high dr (>20 : 1) and an excellent ee (>99%) was achieved but a lower yield was observed regretfully (see ESI† for details).

Scheme 3 Gram-scale cascade reaction.

Conclusions

In summary, we have developed an organocatalytic Michael–Michael–aldol sequence that generated a series of polysubstituted spirocyclohexane oxindoles using a bifunctional squaramide as the catalyst. These structurally complex scaffolds were obtained in good yields (up to 85%) with excellent stereoselectivities (>20 : 1 dr, >99% ee in all cases), featuring the efficient formation of three C–C bonds and six contiguous stereocenters including one all-carbon spiroquaternary stereocenter. We envision that these important skeletons would show great promise in the further synthesis of bioactive molecules.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21302020, 21342009 and 21472019) is gratefully acknowledged.

Notes and references

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10. CCDC 1007247 (for N-Boc-deprotected product of 4b).
11. The proposed transition states for the explanation of stereochemistry outcome.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 1007247. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00299g

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