Dinuclear zinc-catalyzed desymmetric intramolecular aldolization: an enantioselective construction of spiro[cyclohexanone-oxindole] derivatives

Abstract

Based on oxindole-derived diketones as the substrates, asymmetric desymmetrizing intramolecular aldol or aldol condensation reactions are reported, which are catalyzed by a Trost bis-ProPhenol dinuclear zinc complex. The corresponding spiro[cyclohexanone-oxindole] derivatives were obtained in good yields with moderate to good enantioselectivities.

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Introduction

The aldol or aldol condensation, which provides practical β-hydroxycarbonyl skeleton or α,β-unsaturatured carbonyl compounds, is one type of classic carbon–carbon bond formation reaction and has been developed into an indispensable and efficient tool in organic synthesis.¹ Numerous catalysts of the aldol reaction, including enzymes,² metal complexes³ and small molecules,⁴ have been reported. The mechanism of some metal-catalyzed direct asymmetric aldol reactions imitates that of fuculose-1-phosphate aldolase (type II aldolase), which employs a zinc ion to acidify the α-proton of the donor component to form an enolate.⁵ Inspired by the catalysis of fuculose-1-phosphate aldolase, in 2000, Trost and Ito reported a dinuclear zinc catalyst, produced by the use of a ligand known as ProPhenol, for the aldol reaction of aryl methyl ketones with a wide variety of aldehydes with excellent catalytic outcomes.⁶

The asymmetric desymmetrization of meso compounds by enzymatic⁷ and nonenzymatic⁸ methods has proven to be a versatile and powerful strategy in asymmetric synthesis. Asymmetric desymmetrization of diketones was initially reported via organocatalysis by Agami et al. in 1984, albeit the reaction led to cyclohexenone derivatives only with moderate enantioselectivities and in poor yields.⁹ Subsequently, Lerner et al. found that antibody 38C2 was a more active enzymatic catalyst, but the enantioselectivity remained moderate.¹⁰ In 2008, List et al. solved the longstanding problem of enantioselective desymmetrizing aldolizations of 4-substituted 2,6-heptanediones to enantiomerically enriched 5-substituted 3-methyl-2-cyclohexene-1-ones, in which Cinchona alkaloid deriving a primary amine in combination with acetic acid turned out to be efficient and highly enantioselective catalysts to furnish corresponding aldol condensation products in good yields with high enantioselectivities.¹¹

The spirooxindoles represent a large family of alkaloids, natural products and pharmaceutically relevant compounds, which display remarkable structural complexity and interesting biological activity.¹² Consequently, various synthetic protocols have been developed over the past few decades for the construction of multistereogenic spirocyclic oxindoles.¹³ In particular, the spirocyclic oxindole family with a chiral spiro[cyclohexanone-1,3′-indoline] core, an intriguing combination of multistereogenic cyclohexanone and oxindole motifs, is a promising subset with potential bioactivity.¹⁴ In 2009, Melchiorre and co-workers pioneered the syntheses of spiro[cyclohexane-1,3′-indoline]-2′,4-diones via [4 + 2] double Michael additions.¹⁵ Gong et al.,¹⁶ Wang et al.,¹⁷ and our group¹⁸ each reported highly enantioselective syntheses of spiro[cyclohexanone-oxindole] or spiro[cyclohexenone-oxindole] derivatives through organocatalytic cascade transformations. Herein, we report our preliminary results on a desymmetrizing intramolecular aldol reaction for asymmetric synthesis of spiro[cyclohexanone-oxindole] compounds in high yields with moderate to good enantioselectivities.

Results and discussion

Initially, a series of dinuclear zinc catalysts were prepared in situ by the addition of a solution of diethylzinc into a solution of chiral ligands L1–9 (Scheme 1) in o-xylene according to the molar ratio of 2 : 1 at room temperature. Then, these catalysts with 10 mol% catalyst loading were respectively employed in the asymmetric intramolecular aldolization of diketone oxindole 1a in the presence 30 mg of 4 Å molecular sieve (MS) in o-xylene at room temperature. As shown in Table 1, the ligands (R,R)-L1, (R)-L2, (S,S)-L3 and (S,S)-L4 were found to be ineffective for the reaction, affording essentially only trace amounts of the desired products (Table 1, entries 1–4). Subsequently, we tested Trost's dinuclear zinc catalysts for this transformation. The bis-ProPhenol ligands (S,S)-L5–9 were varied with different substituents on (S)-prolinol backbone. The screening results indicated that bis-ProPhenol ligand (S,S)-L9 was the best choice with 30 mg of 4 Å MS in the catalyst solution at room temperature for 12 hours, which provided the desired product 2a in 80% yield and 1 : 10 dr, 97% ee (Table 1, entry 9 vs. entries 1–8). When 3 Å MS or 13 Å MS was introduced into the reaction, or without MS, poorer catalytic results were observed (Table 1, entries 10–12).

Scheme 1 Screened ligands.

Table 1 Optimization of dinuclear zinc catalysts

Entry^a	Ligand	Additive	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol), L (10 mol%), ZnEt2 (20 mol%), and 30 mg MS in o-xylene (1 mL) for 12 hours at room temperature (30 °C).b Isolated yield.c Determined by ^1H NMR analysis.d Determined by chiral HPLC analysis (Chiralpak AD-H).
1	L1	4 Å MS	18	1 : 4	−15
2	L2	4 Å MS	14	1 : 1.5	29
3	L3	4 Å MS	15	7.3 : 1	0/0
4	L4	4 Å MS	<10	—	—
5	L5	4 Å MS	<10	—	—
6	L6	4 Å MS	20	1 : 2	51
7	L7	4 Å MS	15	15 : 1	40
8	L8	4 Å MS	<10	—	—
9	L9	4 Å MS	80	1 : 10	97
10	L9	3 Å MS	71	1 : 2.9	93
11	L9	13 Å MS	70	1 : 2.9	90
12	L9	None	75	1 : 2.3	85

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Further results on the optimization of other parameters for the intramolecular aldol reaction catalyzed by dinuclear zinc complex ZnEt₂/(S,S)-L9, including reaction medium, catalyst loading and reaction temperature, are summarized in Table 2. Firstly, we found that the reactivity was greatly influenced by the reaction medium (Table 2, entries 1–6). By the use of toluene, o-xylene or diethyl ether as the reaction medium, the reactions proceeded very well to furnish the desired products in 85–90% yields with 1 : 9–1 : 10 dr and 94–97% ee (Table 2, entries 1–3). In comparison, the reactions proceeded in an obviously sluggish manner in m-xylene, THF and CH₂Cl₂, which afforded the desired products in lower yields and with lower ee (Table 2, entries 4–6). In addition, when the reaction temperature was decreased from 30 °C to 20 °C, the diastereoselectivity was dramatically reduced to 1 : 7.3 (Table 2, entry 7). When increasing the reaction temperature to 40 °C, the reaction gave the expected product 2a in 68% yield, albeit with 1 : 20 dr and >99% ee (Table 2, entry 8). Furthermore, on increasing the catalyst loading to 15 mol% or 20 mol%, the ee was not influenced too much but the diastereoselectivity was dramatically reduced (Table 2, entries 9 and 10). However, when the catalyst loading was decreased to 5 mol% or 2.5 mol%, the reaction displayed reduced yield and diastereoselectivity (Table 2, entries 11 and 12). Therefore, 10 mol% of dinuclear zinc catalyst ZnEt₂/(S,S)-L9 and 30 mg of 4 Å MS additive were optimal reaction conditions, which were further employed to investigate the substrate scope of this intramolecular aldolization.

Table 2 Further optimization of reaction parameters

Entry^a	Solvent	Cat. (mol%)	Temp. (°C)	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol), (S,S)-L9 (10 mol%), ZnEt2 (20 mol%) and 30 mg of 4 Å MS in solvents (1 mL) at room temperature (30 °C).b Isolated yield.c Determined by ^1H NMR analysis.d Determined by chiral HPLC analysis (Chiralpak AD-H).
1	Toluene	10	rt	88	1 : 9	94
2	o-Xylene	10	rt	85	1 : 10	97
3	Et2O	10	rt	90	1 : 9	97
4	m-Xylene	10	rt	56	1 : 2.6	87
5	THF	10	rt	56	56 : 44	79
6	CH2Cl2	10	rt	42	1 : 4	87
7	o-Xylene	10	20	80	1 : 7.3	91
8	o-Xylene	10	40	68	1 : 20	>99
9	o-Xylene	20	rt	85	1 : 4.8	95
10	o-Xylene	15	rt	80	1 : 5.6	97
11	o-Xylene	5	rt	50	1 : 6.1	98
12	o-Xylene	2.5	rt	<10	—	—

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The dehydration of the aldol product was also investigated in the presence of some common Brønsted acids, such as HCl, HCOOH, trifluoroacetic acid (TFA), para-toluenesulfonic acid (PTSA) and trifluoromethanesulfonic acid (TfOH). As shown in Table 3, 98% yields were respectively obtained in the presence of 10 equivalents of HCl, PTSA or TfOH (Table 3, entries 1, 4 and 5). However, the dehydration did not take place with HCOOH, and the performance of TFA was proven to be inferior to that of the above mentioned Brønsted acids (Table 3, entries 2 and 3). Finally, hydrogen chloride was selected as an optimal dehydrating regent.

Table 3 The dehydration of the aldol product with Brønsted acids

Entry^a	Brønsted acid (10 equiv.)	Yield^b (%)	ee^c (%)
a Unless otherwise noted, all reactions were carried out with 2a (0.03 mmol), and Brønsted acids (0.3 mmol), in CH2Cl2 (1 mL) for 12 hours at room temperature.b Isolated yield.c Determined by chiral HPLC analysis (Chiralpak AD-H).d 3 h.
1	HCl	98	93
2	HCOOH	No reaction	—
3	TFA	68	93
4	PTSA	98	93
5	TfOH	98	93
6^d	HCl	50	93

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Having established the optimized reaction conditions, we then explored the substrate scope and limitation of the present intramolecular aldol reaction. We found that some aldol products were susceptible to dehydration, generating the corresponding α,β-unsaturated ketone compounds. Thus, it became very difficult to separate them through column chromatography on silica gel. Fortunately, it was found that aldol products 2b–e could be isolated as the pure compounds, and their catalytic results are summarized in Table 4. Substrates 1b–e, bearing electron-donating substituents (–Me, –OMe) on the oxindole backbone, led to their aldol products 2b–e in 56–81% yields with varying levels of diastereoselectivities (1 : 3–1 : 20) and enantioselectivities (82–95%) (Table 4, entries 1–4).

Table 4 Substrate scope examination

Entry^a	R^a	Product	Yield^b (%)	dr^c	ee^d (%)
a Unless otherwise noted, all reactions were carried out with 1 (0.1 mmol), (S,S)-L9 (10 mol%), ZnEt2 (20 mol%) and 30 mg of 4 Å MS in o-xylene (1 mL) at 40 °C.b Isolated yield.c Determined by ^1H NMR analysis.d Determined by chiral HPLC analysis (Chiralpak AD-H).
1	5-CH3	2b	56	1 : 11	95
2	5-OCH3	2c	59	1 : 3	82
3	5,7-2CH3	2d	80	1 : 20	93
4	7-Me	2e	81	1 : 20	86

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Due to the difficulty of isolation of aldol products and dehydration products, the sequential aldol condensation reaction was also investigated. After the aldol reaction was judged to be completed as monitored by TLC stains, ten equivalents of hydrogen chloride were introduced into the reaction mixture. The catalytic results are summarized in Table 5. For substrates 1b–d and 1n bearing –Me or –OMe groups, the reactions proceeded smoothly to provide the desired dehydration products 3b–d and 3n in 64–79% yields with 85–92% ee, respectively (Table 5, entries 1–3 and 13). Halogen atoms such as fluorine, chlorine and bromine on different positions of the oxindole backbones obviously exerted a negative influence on the reaction, which generated the corresponding products 3e–m in 45–70% yields with 63–88% ee (Table 5, entries 4–12). Also, N–Ph and N–Bn protected diketones 1o and 1p were investigated for this sequential aldol condensation reaction, which afforded corresponding products 3o and 3p in 63% and 60% yields with 95% and 89% ee, respectively (Scheme 2). Simultaneously, single crystals of 2a were obtained from ethyl acetate and n-hexane, and the configuration of chiral stereo centers of tertiary alcohol and spiro quaternary carbon was unambiguously determined by X-ray diffraction analysis with Cu Kα radiation (λ = 1.54178 Å) (Fig. 1).

Table 5 Substrate scope examination

Entry^a	R	Product	Yield^b (%)	ee^c (%)
a Unless otherwise noted, all reactions were carried out with 1 (0.1 mmol), (S,S)-L9 (10 mol%), ZnEt2 (20 mol%) and 30 mg of 4 Å MS in o-xylene (1 mL) at 40 °C for 12 hours. Then HCl aq. (1.0 mmol) was added in CH2Cl2 (1 mL) for another 12 hours at room temperature.b Isolated yield.c Determined by chiral HPLC analysis (Chiralpak AD-H or Chiralcel OJ-H).
1	5-CH3	3b	71	87
2	5-OCH3	3c	64	85
3	5,7-2CH3	3d	78	92
4	5-F	3e	63	71
5	5-Cl	3f	70	80
6	5-Br	3g	58	63
7	4-Cl	3h	45	82
8	4-Br	3i	53	88
9	6-Br	3j	68	73
10	6-Cl	3k	55	75
11	7-Cl	3l	68	75
12	7-F	3m	55	82
13	7-Me	3n	79	86

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Scheme 2 Investigation of protecting group effects.

Fig. 1 X-ray crystal structure of product 2a.¹⁹

In conclusion, a series of diketone compounds based on oxindole backbones have been designed and employed for intramolecular desymmetrizing aldol or aldol condensation reactions, which were catalyzed by a Trost dinuclear zinc catalyst. The corresponding reactions proceeded smoothly to provide spiro[cyclohexanone-oxindole] compounds in reasonable yields with moderate to good enantioselectivities.

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), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Scientific and Technologic Infrastructure of Suzhou (SZS201207).

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19. CCDC 1011578 contains the supplementary crystallographic data for this paper†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1011578. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra02296k

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