Organocatalytic asymmetric Henry reaction of isatins: Highly enantioselective synthesis of 3-hydroxy-2-oxindoles

Abstract

Organocatalytic asymmetric Henry reaction of isatins with nitromethane has been achieved with the use of C₆′-OH cinchona alkaloid catalyst, affording 3-substituted 3-hydroxy-oxindoles in excellent yields and high enantioselectivities, and this method was successfully applied to the total synthesis of (R)-(+)-dioxibrassinin.

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3-Substituted 3-hydroxyoxindoles have been found to be crucial structural motifs in a variety of alkaloid natural products and pharmaceuticals (Fig. 1), the biological activities of which are greatly affected by the substituted group at the C₃-position and the absolute configuration of the stereogenic centers.² Therefore, the development of new methodologies for the stereoselective synthesis of chiral 3-hydroxyoxindoles with a certain configuration is of paramount importance. Over the past years, excellent synthetic approaches based on transition-metal catalysis or organocatalysis have been advanced to tackle this synthetic challenge.³ Among all the methods developed, the nucleophilic addition to isatins proves to be the most straightforward one, which has attracted much research interest recently.⁴ In this regard, significant progress has been made on asymmetric aldol reactions for the construction of a chiral 3-hydroxyoxindole scaffold. However, the synthesis of this subunit via a catalytic asymmetric Henry (or nitroaldol) reaction has not been reported until recently.¹

Fig. 1 Selected examples of natural products and bioactive compounds containing 3-substituted 3-hydroxyoxindole motifs.

The catalytic asymmetric Henry reaction provides an efficient strategy for constructing β-nitroalcohols, which are valuable building blocks in the synthesis of complex molecules.⁵ Although significant success has been made with aldehydes as the substrates in the asymmetric Henry reaction, the use of more challenging ketones⁶ as Henry acceptors to construct stereogenic quaternary carbon center⁷ has not been well explored.

Herein, we describe our research on the organocatalytic asymmetric Henry reaction of isatins for the construction of chiral 3-substituted 3-hydroxyoxindoles.^1,8 This methodology was further applied as the key step for the total synthesis of (R)-(+)-dioxibrassinin and the formal synthesis of (S)-(−)-spirobrassinin.

We began our investigation with isatin (1a) and nitromethane (2) as the substrates, and with THF as the solvent for optimising the reaction conditions at 5 °C (Table 1). A series of bifunctional catalysts based on cinchona alkaloid scaffold were screened for this reaction. As shown in Table 1, the reaction catalysed by quinidine (QD) gave the desired product 3a in an almost quantitative yield, but with no enantioselectivity (entry 1); while quinidine-derived thiourea catalyst (QD-2) afforded the product 3a with 42% ee (entry 2). To our delight, the C₆′-OH cinchona alkaloid catalyst⁹ (QD-1a) significantly improved the ee value to 76% (entry 3). This type of organocatalyst with different substituents at the C₉-position (entries 3–8) had a great impact on the enantioselectivity of the product 3a. With –OBz as the substituent at C₉-position, the catalyst QD-1d further improved the enantioselectivity to 88% ee (entry 6). When the catalyst Q-1d was used, another enantiomer of product 3a could be obtained with 87% ee (entry 7). Further improvement of ee value to 92% was found (entry 8), when the catalyst Q-1e^6h with the more electron-withdrawing substituent, R = 3,5-(CF₃)₂-benzoyl, was employed.

Table 1 Screening of catalysts and optimization of reaction conditions.^a

Entry	Catalyst	Solvent	Time (h)	Yield (%)^b	ee (%)^c
a Reaction was performed with 0.1 mmol of 1a, 1.0 mmol of 2 and 10 mol% of catalyst in 1.0 mL of anhydrous solvent under argon. b Isolated yield after purification by column chromatography. c Determined by HPLC analysis using a Daicel chiral AD-H column. d 40 mg of 4 Å MS was added. e 25 μL of H2O was added.
1	QD	THF	5	99	racemic
2	QD-2	THF	5	99	42 (S)
3	QD-1a	THF	24	98	76 (S)
4	QD-1b	THF	36	96	43 (S)
5	QD-1c	THF	24	95	35 (S)
6	QD-1d	THF	36	96	88 (S)
7	Q-1d	THF	36	96	87 (R)
8	Q-1e	THF	84	96	92 (R)
9	Q-1e	EtOAc	60	96	79 (R)
10	Q-1e	Toluene	36	93	57 (R)
11	Q-1e	CH2Cl2	36	93	4 (R)
12	Q-1e	EtOH	20	98	30 (R)
13	Q-1e	Et2O	96	94	82 (R)
14^d	Q-1e	THF	84	96	92 (R)
15^e	Q-1e	THF	84	96	70 (R)

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The influence of different solvents on the reaction was therefore investigated with Q-1e as the catalyst (Table 1, entries 8–14). All the solvents tested proved to be efficient, providing the product with excellent yield, however, the enantioselectivity varied significantly. With EtOAc (entry 9) or toluene (entry 10) as the solvent, the enantioselectivity is moderate. CH₂Cl₂ was not suitable for this reaction and gave an almost racemic product (entry 11). The reaction proceeded much faster in the polar protic solvent, EtOH, but the enantioselectivity is poor (entry 12). Amongst all the solvents screened, ethereal solvents proved to be more suitable for the reaction and THF emerged as the best. The addition of 4 Å molecular sieves (entry 14) did not have an obvious effect on the enantioselectivity. However, the ee value of 3a dramatically dropped in the presence of H₂O (entry 15). Finally, the optimal reaction condition was determined to be: 10 mol% of Q-1e as the catalyst, THF as the solvent, and 5 °C as the reaction temperature.

Next, we turned our focus to the substrate scope and the obtained results are summarised in Table 2. Whether electron-withdrawing or -donating groups at the C₅- or the C₇-position of the unprotected isatins (1a–1i) were employed, the reaction proceeded smoothly to give the product 3 in excellent yields (95–97%) along with high enantioselectivities (84–92% ee). However, for the substrate of 4,7-dichloroisatin (1j), only moderate enantioselectivity (71%) could be obtained. The protecting group on the N-atom also has an effect on the enantioselectivity. Utilization of N-benzyl isatin (1k) decreased the ee value to 76% while N-methyl isatin (1l) provided the corresponding product 3l with 91% ee. When nitroethane was used as the nucleophile, the reaction was rather slow and only 23% yield, 3 : 1 dr and 5% ee were obtained after 5 days under the optimal reaction conditions. The enantiopure product of 3g (>99% ee) was obtained by slow recrystallisation from a mixture of acetone and hexane and the obtained single-crystals were suitable for X-ray analysis. As shown in Fig. 2, the absolute configuration of the quarternary carbon centre in the product 3g was determined to be R.¹⁰

Fig. 2 The X-ray single-crystal structure of the product 3g.

Table 2 Substrate scope.^a

a The reaction was performed with 0.1 mmol of 1, 1.0 mmol of 2 and 10 mol% of catalyst Q-1e in 1 mL of anhydrous THF under argon. Yield refers to the isolated product. Enantiomeric excess was determined by HPLC analysis using a Daicel chiral AD-H or OJ-H column. b After recrystallisation.

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We have applied the above method to realise the catalytic asymmetric total synthesis of (R)-(+)-dioxibrassinin, which can be further transformed to (S)-(−)-spirobrassinin.^1,11 As shown in Scheme 1, the use of isatin 1a as the substrate under optimised scale-up conditions gave the Henry product 3a with 95% yield and 91% ee. The product 3a was further reduced to the corresponding amino alcohol using Zn/HOAc conditions. We found that, after the treatment with HCl, the reaction residue could be directly used for the next transformation without isolation. In the presence of pyridine, the previous mixture was treated with CS₂ and followed by MeI to give (R)-(+)-dioxibrassinin with 65% yield and 89% ee over two steps.

Scheme 1 Asymmetric total synthesis of (R)-(+)-dioxibrassinin and formal synthesis of (S)-(−)-spirobrassinin.

In summary, we have developed an organocatalytic asymmetric Henry reaction of isatins and nitromethane by using C₆′-OH cinchona alkaloid catalyst. A variety of chiral 3-substituted 3-hydroxyoxindoles have been successfully synthesized in excellent yields and high enantioselectivities. This method was further applied in the total synthesis of (R)-(+)-dioxibrassinin.

Acknowledgements

The National Natural Foundation of China (No. 20972064) is gratefully acknowledged for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available: representative experimental procedures, full characterization of all novel compounds, crystallographic data of compound 3g. CCDC reference number 828228. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1ra00477h

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