Formal [3 + 2] cycloaddition of α-unsubstituted isocyanoacetates and methyleneindolinones: enantioselective synthesis of spirooxindoles

Abstract

The first enantioselective formal [3 + 2] cycloaddition of α-unsubstituted isocyanoacetates with protecting-group-free methyleneindolinones was developed. A variety of optically enriched 3,3′-pyrrolidinyl spirooxindoles were obtained in excellent yields, and diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr, 99% ee) with low catalyst loading under mild reaction conditions.

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We have been pursuing the development of asymmetric enolate methodologies for the synthesis of heterocyclic compounds for several years.¹ There have been many approaches to generate chiral enolate intermediates. For example, the nucleophilic addition of N-heterocyclic carbenes (NHCs)² or cinchona alkaloid derivatives³ to ketenes or vinyl ketenes afforded 1,2-dipole enolates or dienolates, serving as 1,4-dipole enolates,^4,2e respectively. Our recent efforts have focused on the use of functionalized 1,3-dipole enolates derived from isocyanoacetate, due to its isocyanide group and acidic α-CH fragment encountered chiral Brønsted base.^1d,e

Recently, the cyclization of methyleneindolinones has emerged as a powerful tool for the construction of indole-fused heterocyclic compounds or spirooxindoles.^4b,5 In 2010, Ye and co-workers reported the NHC-catalyzed formal [4 + 2] cycloaddition of ketenes with methyleneindolinones, as surrogates of “1,4-dipole”, to synthesize indole-fused dihydropyranones (Scheme 1, 1a).^5g In 2013, they developed the cinchona alkaloid catalyzed [4 + 2] cyclization of α,β-unsaturated acyl chlorides with methyleneindolinones, as surrogates of “1,2-dipole”, to produce spirocarbocyclic oxindoles (Scheme 1, 1b).^4b We reasoned that the 1,3-dipole enolate generated from isocyanoacetate may facilitate a [4 + 3] or [3 + 2] cycloaddition with methyleneindolinone to afford a indole-fused seven-membered heterocycle skeleton⁶ or spirooxindole,⁷ which are both privileged structure moieties found in many biologically active natural products and pharmaceutically important compounds (Scheme 1, 2a, 2b).

Scheme 1 Inspiration for cyclization of isocyanoacetates with methyleneindolinones.

Initial exploration utilizing methyleneindolinone 1 and the commercially available methyl isocyanoacetate 2a employing Dixon's catalysis system led to a [3 + 2] cyclization affording 3,3′-pyrrolidinyl spirooxindole 3, whereas no [4 + 3] annulation product was observed (Scheme 2). The 3,3′-pyrrolidinyl spirooxindole scaffold is an important backbone in the spirooxindole family because of not only its interesting biological activities, but also its versatility as an intermediate in the synthesis of related and more sophisticated spirooxindole structures.^5,7

Scheme 2 Cycloaddition of methyleneindolinone with methyl isocyanoacetate.

Recently, Wang,^5a Zhong^5b and Yan^5cet al. developed stereoselective [3 + 2] cycloadditions of α-aryl isocyanoacetates with active protected methyleneindolinones to access 3,3′-pyrrolidinyl spirooxindoles catalyzed by cinchona alkaloid-based thiourea tertiary amines, respectively (Scheme 3). Notably, the isocyanoacetates bearing α-aryl substituents are crucial for achieving good reactivity and enantioselectivity in this catalytic system. Furthermore, to the best of our knowledge, the synthetic methodology to enantioselectively construct this rigid spiroarchitecture utilizing α-unsubstituted and α-alkyl isocyanoacetates is not available. Herein we report the first highly enantioselective formal [3 + 2] cycloaddition reaction of α-unsubstituted and α-alkyl isocyanoacetates with less active methyleneindolinones catalyzed by a chiral silver(I) complex developed by the group of Dixon.⁸

Scheme 3 [3 + 2] Cycloaddition of methyleneindolinones with α-aryl isocyanoacetates.

To further optimize the reaction conditions, the protecting-group-free methyleneindolinone 4a was chosen as the model substrate because of its easy synthesis.⁹ As shown in Table 1, several catalysts or ligands were screened to evaluate their ability to promote the Michael/cyclization reaction sequence of 2a and 4a at ambient temperature. To our disappointment, no desired [3 + 2] cyclization product 5a was obtained in the presence of quinine (6a) or the quinine-based thiourea tertiary amine (6b), respectively (entries 1 and 2). 6b proved to be an excellent catalyst in asymmetric cyclization of α-aryl isocyanoacetates,^5a–c but was unable to activate the α-unsubstituted isocyanoacetates and hence was catalytically inactive for the reaction. Although a chiral silver complex with (S)-MOP 6c was the optimal catalyst in Gong's work of the enantioselective formal [3 + 2] cycloaddition reaction of α-aryl isocyanoacetates with 2-oxobutenoate esters,¹⁰6c with AgOAc failed to promote the reaction (entry 3). Interestingly, 6c with Ag₂O afforded the desired product in good yield though with poor diastereo- and enantioselectivities (entry 4). Inspired by the recent report from the group of Dixon on enantioselective isocyanoacetate cycloaddition catalyzed by a silver(I) complex with cinchona-derived amino phosphine precatalysts,⁸ we tested the related compounds 6d–f for our reaction. To our great delight, all these precatalysts with Ag₂O led to excellent yields, diastereo- and enantioselectivities (entries 5–7). Lowering the loading of 6e and Ag₂O had a negligible impact on the enantioselectivities (entries 8 and 9). A survey of solvents identified AcOEt as the most suitable media (entries 10–13). Increasing the concentration of the catalysts benefited the diastereoselectivity (entry 14), and much higher diastereoselectivity (trans/cis > 20 : 1) was obtained via slow addition of methyl isocyanoacetate 2a to the mixture of the silver(I) complex and methyleneindolinone 4a over 5 hours.

Table 1 Optimization of reaction conditions^a

Entry	6 (X)	[Ag] (Y)	Solvent	Yield^b [%]	trans/cis^c	ee^d [%]
a Reaction conditions: 2a (0.4 mmol), 4a (0.4 mmol), solvent (2 mL). b Total yields of the isolated trans and cis-isomers. c Determined by ^1H NMR spectroscopy (400 MHz) of the reaction mixture. d ee of the trans-isomer determined by HPLC analysis using a chiral stationary phase. e AcOEt 0.4 mL. f 2a (0.4 mmol) in AcOEt (0.4 mL) was added via a syringe pump over 5 h.
1	6a (10)	0	THF	0	—	—
2	6b (10)	0	THF	0	—	—
3	6c (12)	AgOAc (10)	THF	0	—	—
4	6c (12)	Ag2O (5)	THF	84	4 : 1	31
5	6d (20)	Ag2O (10)	THF	99	7 : 1	−93
6	6e (20)	Ag2O (10)	THF	99	7 : 1	95
7	6f (20)	Ag2O (10)	THF	99	6 : 1	−94
8	6e (10)	Ag2O (5)	THF	99	7 : 1	94
9	6e (5)	Ag2O (2.5)	THF	99	7 : 1	94
10	6e (5)	Ag2O (2.5)	CH2Cl2	99	7 : 1	89
11	6e (5)	Ag2O (2.5)	MTBE	93	6 : 1	92
12	6e (5)	Ag2O (2.5)	Toluene	96	7 : 1	95
13	6e (5)	Ag2O (2.5)	AcOEt	99	7 : 1	95
14^e	6e (5)	Ag2O (2.5)	AcOEt	99	13 : 1	95
15^e^,^f	6e (5)	Ag2O (2.5)	AcOEt	99	>20 : 1	95

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With the established optimal reaction conditions, a variety of 3,3′-pyrrolidinyl spirooxindoles were synthesized and the results are summarized in Table 2. Isocyanoacetates bearing different ester groups were all suitable substrates, producing the corresponding products 5a–d in uniformly high yields with excellent diastereoselectivities and enantioselectivities. Different substitution patterns on the aryl ring of methyleneindolinones were well tolerated (5e–i). As expected, these substrates underwent smooth cycloaddition reactions to give the spirooxindoles, whereas both diastereoselectivity and enantioselectivity showed some dependence on the electronic feature of the substituents. The substrates with electron-withdrawing substituents (Cl, Br) afforded the products in excellent yields, dr and ee values (5e, 5f). When Bz was introduced, the yield and diastereoselectivity were still very high, albeit the ee value decreased (5g). In the methyleneindolinones bearing electron-donating substituents (Me, MeO), the diastereo- and enantioselectivities were slightly decreased without eroding the yield (5h, 5i). When the two methyl groups of methyleneindolinone were replaced by two ethyl groups, the reaction proceeded smoothly, thus providing product 5j with good stereocontrol and in excellent yield. It is worth noting that all the reactions were carried out under an ambient atmosphere, and exclusion of air or moisture was not required.

Table 2 The reaction scope of the enantioselective formal [3 + 2] cycloaddition of 2 and 4^a,b,c

a Total yields of the isolated trans and cis-isomers. b dr determined by ¹H NMR spectroscopy (400 MHz) of the reaction mixture. c ee of the trans-isomer determined by HPLC analysis using a chiral stationary phase. See the ESI for details.

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Notably, the formed cycloaddition products are highly functionalized, along with an imine moiety which is easy for further structural modifications. As shown in Scheme 4, when product 5e was treated with NaBH₃CN, it was readily transformed into 3,3′-pyrrolidinyl spirooxindole 7 in nearly quantitative yield without loss of diastereo- and enantioselectivities, and its X-ray crystallographic analysis¹¹ confirmed the relative and absolute configurations of the cycloaddition products 5a–j.

Scheme 4 Transformation of the cycloadduct.

The formal [3 + 2] cycloaddition of isocyanoacetates is not limited to the coupling with disubstituted 3-methyleneindolinones. Mono-substituted (phenyl, methyl) 3-methyleneindolinones are also suitable partners, and provided the corresponding cycloadducts in excellent yields and with good to excellent diastereo- and enantioselectivities (Scheme 5). More interestingly, although we noticed that a similarly excellent yield, enantioselectivity and switched diastereoselectivity were obtained when the reactions were conducted with E-4i and Z-4i, and a reversal of the absolute configuration of the 4′-position was observed (5l, 5m). These results suggest that these two substrates have the same mode of enantiofacial selection and that the olefin geometry does not play a major role in determining the facial selectivity of the cyclization. The relative configurations of the products were assigned by the NOE interactions of the two isomers (see the ESI† for details).

Scheme 5 [3 + 2] Cycloaddition of monosubstituted-4 and methyl isocyanoacetate 2a.

We have explored the possibility that the isocyanoacetate can bear α-alkyl substituents, e.g., α-methyl. To the best of our knowledge, α-alkyl substituted isocyanoacetates were inactive in the reported transformations of this type, due to the decreased acidity of the α-hydrogen atoms in these isocyanoacetates.^5a In fact, the use of α-methyl isocyanoacetate 2e could also lead to a smooth formal [3 + 2] cycloaddition with methyleneindolinone in excellent yield, good diastereo- and enantioselectivities (Scheme 6). Most specifically, the unsubstituted 3-methyleneindolinone 4j could also be used as a reaction partner with 2e providing the spiro compound, which is too unstable to be purified. The crude product was then reduced with NaBH₃CN and the resulting amine was protected with the p-toluenesulfonyl (Ts) group to generate 3,3′-pyrrolidinyl spirooxindole 8 in 48% yield over three steps with 73% ee and 2 : 1 diastereoselectivity. Unfortunately, despite vigorous efforts, a qualified single crystal of 5o or 8 for X-ray crystallographic analysis could not be obtained. Thus, the absolute configuration of these products has not been assigned. Systematic optimization of the formal [3 + 2] cycloaddition reaction of α-alkyl isocyanoacetates with methyleneindolinones is ongoing, and the results will be reported in due course.

Scheme 6 [3 + 2] Cycloaddition of methyleneindolinones and α-methyl isocyanoacetates.

In summary, we have developed the first enantioselective formal [3 + 2] cycloaddition reactions of α-unsubstituted isocyanoacetates with the less active protecting-group-free methyleneindolinones using mild reaction conditions. A variety of optically enriched 3,3′-pyrrolidinyl spirooxindoles were obtained in excellent yields, diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr, 99% ee). The high efficiency of this process, coupled with operational simplicity, makes it an attractive method for spirooxindole synthesis. Further studies on expanding the application of this approach to synthesize more promising candidates for drug discovery as well as the biological evaluation are in progress. The asymmetric formal [4 + 3] cycloaddition of isocyanoacetates with methyleneindolinones is underway in our lab.

The work described here was supported by the National Natural Science Foundation of China (21372267, 21402150 and 21572027) and the Singapore National Research Foundation (NRF Fellowship).

Notes and references

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11. CCDC 1496241 contains the supplementary crystallographic data for compound 7. Selected data are also included in the ESI.†.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, spectral data of new compounds, and crystallographic data. CCDC 1496241. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00555a

‡ These authors contributed equally to this work.

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