Chiral Calcium-Catalyzed Asymmetric Epoxidation Reactions Using Hydrogen Peroxide as the Terminal Oxidant

Abstract

Asymmetric epoxidation reactions of chalcone derivatives catalyzed by chiral calcium complexes using hydrogen peroxide were developed. The epoxidation reactions proceeded smoothly to afford the desired products in good yields with good enantioselectivities. This is the first example of chiral calcium-catalyzed asymmetric epoxidation reactions using hydrogen peroxide as the terminal oxidant.

Alkaline earth metals, which are ubiquitous elements in the natural world,^1,2) are inexpensive, highly abundant, and exhibit lower health and environmental toxicity. In addition, compounds of these metals have high tolerance toward oxygen and moisture. Despite these potential advantages, the use of alkaline earth metals as catalysts in synthetic organic chemistry has been overshadowed by their transition-metal counterparts. Recently, there has been renewed interest in the development of asymmetric catalysts based on alkaline earth metals, particularly those of calcium (Ca), strontium (Sr), and barium (Ba).^3,4) On the other hand, the development of nontoxic chiral metal catalysts for realizing environmentally benign chemical processes is in high demand, especially for continuous-flow fine organic synthesis of drugs, to avoid contamination of the product with metallic impurities.^5,6) Among the alkaline earth metals, Ca is a safe metal that is used in daily life. Our group has been focusing on the development of catalytic carbon–carbon bond-forming reactions using chiral alkaline earth metal catalysts, especially, chiral calcium catalysts, and high enantioselectivities have been achieved.^7–20)

Asymmetric epoxidation reactions of alkenes are one of the most commonly used oxidation reactions for the formation of epoxides; by using this approach, two stereogenic centers can be introduced into the substrate in one step.^21–24) Epoxides also can be easily converted into useful synthetic intermediates through ring-opening processes during nucleophilic substitution reactions.²⁵⁾ Since the pioneering work by Sharpless et al.,^26,27) there have been many reports of successful catalytic asymmetric epoxidation reactions. Among them, asymmetric epoxidation reactions using hydrogen peroxide are ideal from an atom-economical perspective because only H₂O forms as a co-product during the reaction.^28,29) On the other hand, although many successful examples of asymmetric epoxidation reactions using chiral catalysts have been reported, there is only one example of the asymmetric epoxidation reaction using a chiral calcium catalyst. In 2003, Kumaraswamy et al. reported asymmetric epoxidation reactions with tert-butyl hydrogen peroxide using a chiral calcium catalyst prepared from a 1,1′-bi-2-naphthol (BINOL) derivative.³⁰⁾ In this system, however, enantioselectivity was not high, and the use of tert-butyl hydrogen peroxide was less atom-economical compared with hydrogen peroxide. Here, we report our recent efforts to realize more atom-economical, chiral calcium-catalyzed asymmetric epoxidation reactions of chalcone derivatives using hydrogen peroxide as the terminal oxidant (Chart 1).

Chart 1

We investigated the asymmetric epoxidation reaction of chalcone (1a) using an aqueous hydrogen peroxide solution (aq. H₂O₂) (Table 1). As a chiral calcium catalyst, we employed a chiral calcium–Pybox complex prepared from calcium triflate (Ca(OTf)₂) and Indapybox L1, which is a calcium complex that is tolerant toward water. Firstly, in the presence of the chiral calcium complex, the epoxidation reaction of 1a was conducted in methanol (MeOH) using diisopropylethylamine (ⁱPr₂NEt) as a base catalyst. Although the reaction proceeded at −10°C, the reaction was very slow and the enantioselectivity was very low (entry 1). We then examined the effect of solvents. The reaction in ethanol (EtOH) also proceeded, and a slightly improved enantiomeric excess (ee) was achieved (entry 2). When polar aprotic solvents were tested instead of the alcohol solvents, lower reactivity was observed; however, 1,4-dioxane was found to be a promising solvent (entry 5). We next investigated a mixed solvent system of 1,4-dioxane and an alcohol solvent (entries 6–9). Among the systems investigated, a MeOH–1,4-dioxane (1 : 1) mixed system was found to be the most effective, and both good yield and good enantioselectivity were observed (entry 6). Although use of the EtOH–1,4-dioxane mixed (1 : 1) system also led to good enantioselectivity, the reactivity decreased significantly (entry 7). Other mixed solvent systems with isopropyl alcohol (ⁱPrOH) as a bulkier alcohol, or with H₂O did not give good results (entries 8 and 9). Based on the results of these experiments, we concluded that the MeOH–1,4-dioxane (1 : 1) system was optimal for this reaction. Further optimization of the reaction conditions was conducted. To improve the yield, we conducted the reaction for longer reaction time and at increased reaction temperature; however, the yields were not improved (entries 10 and 11). We thought that the lower yields might be ascribed to deactivation of the employed reagents, ⁱPr₂NEt and aq. H₂O₂, which could react with each other to form an amine N-oxide species during the reaction. Therefore, we investigated the addition of further ⁱPr₂NEt and H₂O₂ to the reaction system; however, this was not effective even when the reagents were added at intervals (entries 12–14). Addition of a drying reagent, CaSO₄, to remove water was also not effective (entry 15). Finally, to enhance the reactivity, alternative Lewis acidic calcium salts were examined. To our delight, the yield was improved significantly with good enantioselectivity being maintained when calcium bis(trifluoromethanesulfonyl)imide (Ca(NTf₂)₂) or calcium bis(nonafluorobutanesulfonyl)imide (Ca(NNf₂)₂) was employed as the calcium source³¹⁾ (entries 16 and 17).

Table 1. Optimization of Reaction Conditions^a)

Entry	Solvent	Conditions	Yield (%)	ee (%)
1	MeOH	−10°C, 48 h	50	11
2	EtOH	−10°C, 48 h	50	34
3	THF	−10°C, 48 h	trace
4	MeCN	−10°C, 48 h	9	−3
5	Dioxane	25°C, 48 h	21	42
6	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	66	70
7	EtOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	26	72
8	iPrOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	NR	—
9	H2O/1,4-Dioxane (1 : 1)	25°C, 48 h	41	0
10	MeOH/1,4-Dioxane (1 : 1)	−10°C, 72 h	69	70
11	MeOH/1,4-Dioxane (1 : 1)	25°C, 48 h	60	53
12b)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	19	65
13c)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	55	72
14d)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	58	70
15e)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	61	71
16f)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	83	74
17g)	MeOH/1,4-Dioxane (1 : 1)	−10°C, 48 h	81	74

a) The reaction of 1a with aq. H₂O₂ (1.55 equiv.) was conducted using ⁱPr₂NEt (24 mol%) in the presence of a chiral calcium complex prepared from Ca(OTf)₂ (10 mol%) and L1 (11 mol%) unless otherwise noted. b) ⁱPr₂NEt (48 mol%) was used. c) Further ⁱPr₂NEt (24 mol%) was added after 24 h. d) Further ⁱPr₂NEt (24 mol%) and H₂O₂ (1.55 equiv.) were added after 24 h. e) CaSO₄ (25 mol%) was used as a drying reagent. f) Ca(NTf₂)₂ was used instead of Ca(OTf)₂. g) Ca(NNf₂)₂ was used instead of Ca(OTf)₂.

The substrate scope of this epoxidation reaction was then examined (Table 2). First, we used chalcone derivatives bearing substituents on the phenyl group next to the carbonyl moiety, 4-nitro-substituted chalcone 1b, 4-fluoro-substituted chalcone 1c, and 4-bromo-substituted chalcone 1d. The desired products 2b–d were obtained in similar yields and enantioselectivities. In contrast, when chalcone derivatives bearing electron-donating groups were employed, the desired products 2e and 2f were obtained, albeit in lower yields. Chalcone derivatives bearing other aromatic groups and an alkyl group were also examined. When chalcone derivatives bearing 2-naphthyl and 2-furyl groups instead of the phenyl group were employed, the desired products 2g and 2h were obtained with moderate enantioselectivities. However, the use of substrate 1i, bearing a methyl group, gave none of the desired adduct. We then examined chalcone derivatives bearing substituents on the phenyl group next to the olefin moiety. When 4-nitro-substituted chalcone 1j, 4-fluoro-substituted chalcone 1k, 4-bromo-substituted chalcone 1l, and 4-trifluoromethyl-substituted chalcone 1m were used, the desired products 2j–m were obtained in good yields with moderate to good enantioselectivities. Chalcone derivative 1n, bearing a 4-methyl group, gave the desired adduct 2n with good enantioselectivity. When chalcone derivative 1o, bearing a 4-fluoro group on both phenyl groups was tested, moderate yield and enantioselectivity were obtained. The reaction of 2-benzylidene-1-tetralone (1p) gave the desired product 2p with moderate selectivity; however, the yield was low. It was revealed that many chalcone derivatives were applicable for the chiral calcium-catalyzed asymmetric epoxidation reactions.

Table 2. Substrate Scope

A Proposed catalytic cycle is shown in Chart 2. The chiral calcium complex A prepared from a calcium salt and a Pybox ligand reacts with H₂O₂ in the presence of the amine base to form complex B. Chalcone derivative 1 coordinates with B to form complex C, and a nucleophilic 1,4-addition of the peroxide part to the activated double bond followed by an intramolecular attack of the enolate intermediate D to oxygen atom forms the desired product 2 and H₂O to regenerate the original calcium complex A.³⁰⁾

Chart 2. Proposed Catalytic Cycle

In conclusion, we have developed asymmetric epoxidation reactions catalyzed by chiral calcium complexes using hydrogen peroxide as the terminal oxidant. By using the calcium–Indapybox complex, the desired epoxides derived from chalcone derivatives were obtained in moderate to good yields with moderate to good enantioselectivities. This is the first example of asymmetric epoxidation reactions catalyzed by a chiral calcium complexe using hydrogen peroxide as the terminal oxidant. Further investigations to improve the enantioselectivity and to apply the reaction to continuous-flow synthesis are ongoing.

Experimental

Experimental details are described in Supplementary Materials on the website of this communication.

Acknowledgments

This work was partially supported by a Grant-in-Aid for Science Research from the Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Japan Science and Technology Agency (JST). J. M. thanks JSPS Postdoctoral Fellowships for Research in Japan for financial support.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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