Enantioselective Cyclopropanation of a Wide Variety of Olefins

Article pubs.acs.org/accounts

Enantioselective Cyclopropanation of a Wide Variety of Olefins Catalyzed by Ru(II)−Pheox Complexes Soda Chanthamath* and Seiji Iwasa* Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Tempaku-cho, Toyohashi, Aichi 441-8580, Japan CONSPECTUS: The transition-metal-catalyzed asymmetric cyclopropanation of olefins with diazoacetates has become one of the most important methods for the synthesis of optically active cyclopropane derivatives, which are key pharmaceutical building blocks and present in a large number of natural products. To date, significant progress has been made in this area of research, and efficient stereocontrolled synthetic approaches to cyclopropane derivatives have been developed using rhodium, ruthenium, copper, and cobalt catalysts. However, the vast majority of these strategies are limited to electron-rich olefins, such as styrene derivatives, due to the electrophilicity of the metal−carbene intermediates generated from the reaction of the metal with the diazo compound. Recently, the D2symmetric Co(II)−phophyrin complexes developed by Zhang et al. were shown to be the most efficient catalysts for the asymmetric cyclopropanation of electron-deficient olefins. This catalytic system is mechanistically distinct from the previous rhodium and copper catalytic systems, proceeding via radical intermediates. However, the asymmetric cyclopropanation of vinyl carbamates, allenes, and α,β-unsaturated carbonyl compounds has rarely been reported. Therefore, the development of new powerful catalysts for the asymmetric cyclopropanation of a wide range of olefinic substrates is the next challenge in this field. In this Account, we summarize our recent studies on the Ru(II)−Pheox-catalyzed asymmetric cyclopropanation of various olefins, including vinyl carbamates, allenes, and α,β-unsaturated carbonyl compounds. We demonstrate that the developed catalytic system effectively promotes the asymmetric cyclopropanation of a wide variety of olefins to produce the desired cyclopropane products in high yields with excellent stereocontrol. The use of succinimidyl-, ketone-, and ester-functionalized diazoacetates as carbene sources was found to be crucial for the high stereoselectivity of the cyclopropanation reactions. In addition, we describe reusable chiral Ru(II)−Pheox catalysts, namely, water-soluble Ru(II)−hm-Pheox and polymer-supported PS-Ru(II)−Pheox, which can be reused at least five times in inter- and intramolecular cyclopropanation reactions without any significant loss of catalytic activity or enantioselectivity. These Ru(II)−Pheox-catalyzed asymmetric cyclopropanation reactions provide an elegant method to access a series of optically active cyclopropane derivatives, including cyclopropylamines, dicarbonyl cyclopropanes, alkylidenecyclopropanes, and cyclopropane-fused γ-lactones, which are intermediates in the syntheses of various biologically active compounds. The novel chiral Ru(II)−Pheox complexes are readily synthesized in high yield from inexpensive, commercially available benzoyl chloride and amino alcohols, then fully characterized using X-ray diffraction analysis, NMR, and elemental analysis. These catalysts are easy to handle and stable under ordinary temperatures and conditions and can be used after three months of storage without any loss of catalytic activity or stereoselectivity.

1. INTRODUCTION The cyclopropane ring is an important structural motif commonly found in biologically active compounds, including natural products and pharmaceuticals.1 Thus, the development of synthetic methodologies for cyclopropane construction has attracted much attention during the past two decades.2 Among the various methods reported, the transition-metal-catalyzed asymmetric cyclopropanation of olefins with diazoacetates is a particularly powerful transformation, providing direct access to a wide variety of chiral cyclopropane derivatives, such as cyclopropylamines, alkylidenecyclopropanes, and dicarbonyl cyclopropanes, which are important components in many pharmaceuticals and bioactive molecules (Figure 1).3 Since the pioneering work of Nozaki et al.,4 significant effort has been devoted to developing the highly stereoselective cyclopropana© 2016 American Chemical Society

tion of olefins via carbene transfer catalyzed by copper, rhodium, ruthenium, and cobalt complexes.2 Electron-rich styrene derivatives are usually employed as the olefinic substrate due to their high reactivity toward the electrophilic metal−carbene intermediate. In contrast to the excellent results achieved with styrene derivatives, which have been described in more than 300 reports over the last two decades (counting all publications with any reference to styrene addition), vinyl carbamates,5 allenes,6 and α,β-unsaturated carbonyl compounds7 have rarely been used in asymmetric cyclopropanation reactions (Scheme 1). Therefore, the development of new powerful catalysts with broad substrate scope is the next Received: February 9, 2016 Published: September 20, 2016 2080

DOI: 10.1021/acs.accounts.6b00070 Acc. Chem. Res. 2016, 49, 2080−2090

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Accounts of Chemical Research

Recently, we reported that the Ru(II)−Pheox complex 4a, bearing a metal−carbon σ-bond, is an extremely efficient catalyst for asymmetric inter- and intramolecular cyclopropanation reactions (Figure 2).11a,b In general, C2-symmetric

Figure 1. Examples of biologically active cyclopropanes.

Scheme 1. Previous Reports of the Asymmetric Cyclopropanation of Olefins

Figure 2. Ru(II)−Pheox catalysts.

challenge in this field. In this context, a major breakthrough, the cyclopropanation of electron-deficient olefins, was reported by Zhang et al. using a Co(II)−porphyrin catalyst,7a which proved to be a general and effective catalyst for the asymmetric cyclopropanation of various electron-deficient olefins, forming electrophilic cyclopropane products in high yields and with high stereoselectivities. Acceptor carbene complexes, generated from the reaction of transition-metal catalysts with diazo compounds bearing electron-withdrawing groups such as esters, are highly reactive species and have been proposed as key intermediates in many synthetically useful transformations.8 In these carbenoid or metal−carbene species, chemical interactions occur through σtype electron donation from the carbene carbon to an empty metal d-orbital of the metal and π-electron back-bonding to the empty p-orbital of the carbene carbon (Scheme 2).9 Thus, the metal−carbene complexes formed in situ are expected to be highly electrophilic and, therefore, more reactive toward electron-rich olefins in asymmetric cyclopropanation reactions.10

catalysts are usually preferred over C1-symmetric catalysts for enantioselective transformations, but our results showed that this is not always true in asymmetric cyclopropanation. In 1998, Nishiyama et al. reported a highly enantioselective cyclopropanation using C1-symmetric Ru(II)−Pybox catalysts, explaining that the major carbene intermediate, in which the ester group was anti to the bulky substituent of the ligand, might be selectively attacked by olefins from the third quadrant (Figure 2).11c Although, the enantioselectivities were still lower than those obtained with the corresponding C2-symmetric analogues, this important report illustrated the potential of C1symmetric catalysts. We developed a class of Ru(II)−Pheox catalysts with a stereodirecting unit attached to the oxazoline ring (blue) and featuring various substituents on the ligand backbone to control the electron density on the metal center (red) (Figure 2). Two factors cause different reactivities between Ru(II)−Pheox and traditional catalysts: (i) the design of the chiral ligand environment of the Ru(II)−Pheox catalyst, which allows much closer access to the substrate compared with traditional catalysts to provide a better reaction environment, and (ii) the strong electron-donating effect of the Csp2 anionic ligand on the Ru atom, which facilitates oxidative addition (usually the rate-limiting step of transition-metalcatalyzed reactions). Herein, we recount and analyze our recent efforts in the development of the Ru(II)−Pheox-catalyzed asymmetric cyclopropanation of various olefins, including vinyl carbamates, allenes, and α,β-unsaturated carbonyl compounds. This catalytic system provided an elegant approach to a series of

Scheme 2. Carbene Complex Intermediates

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Accounts of Chemical Research optically active cyclopropane derivatives, such as cyclopropylamines, dicarbonyl cyclopropanes, alkylidenecyclopropanes, and cyclopropane-fused γ-lactones. In addition, we present reusable chiral Ru(II)−Pheox catalysts, namely, water-soluble Ru(II)−hm-Pheox 5 and polymer-supported PS-Ru(II)-Pheox 6, which can be reused at least five times in inter- and intramolecular cyclopropanation reactions without a considerable decrease in catalytic activity or enantioselectivity.

unhindered EDA as the carbene source, high stereoselectivities were achieved. After successfully using succinimidyl diazoacetate (SDA) as a carbene source for the highly trans-selective cyclopropanation reported by Zhang et al.,14 we also found that exceptional transselectivity (>99:1 dr) could be achieved using the Ru(II)− Pheox catalytic system with different styrene derivatives (Scheme 3).11b Moreover, the reaction proceeded rapidly

2. CYCLOPROPANATION OF STYRENE DERIVATIVES Styrene derivatives are commonly used as olefinic components in asymmetric cyclopropanation via transition-metal-catalyzed carbene transfer from diazo compounds.2 Highly stereoselective cyclopropanation reactions of styrene derivatives with sterically demanding diazoacetates, such as tert-butyl, menthyl, and BHT diazoacetates, have been widely reported. In particular, Nishiyama et al. demonstrated that Ru(II)−Pybox complexes were general and efficient catalysts for a high degree of transselectivity in the cyclopropanation of menthyl diazoacetate.12 However, the use of nonbulky ethyl diazoacetate (EDA) as a carbene source usually decreases the diastereo- and enantioselectivity of various catalytic systems; Scott’s Ru-Schiff-base, Buono’s Cu-iminodiazaphospholidine, and Lo’s Ru-porphyrin catalysts provided excellent trans-selectivities and enantioselectivities.13 In this Account, we describe our studies of the asymmetric cyclopropanation of commercially available EDA with styrene derivatives in the presence of Ru(II)−Pheox catalysts (Table 1). After screening the catalysts and the effect of temperature,

Scheme 3. Cyclopropanation of Styrene Derivativesa

Table 1. Cyclopropanation of Styrene Derivativesa

a

under mild conditions in the presence of 1 mol % catalyst to produce the corresponding succinimidyl cyclopropanecarboxylates in high yields (up to 98%) with high enantioselectivities (up to 99% ee). Although the exact mechanism for the high level of diastereocontrol achieved with this catalytic system is not clearly understood, 11d these results indicated the importance of using a carbonyl-functionalized diazoacetate as the carbene source and prompted us to synthesize a variety of functionalized diazoacetates to be explored as carbene sources in the asymmetric cyclopropanation of various olefins in future studies.

ee (%) entry

Ru(II)−Pheox

temp (°C)

yield (%)

trans/cis

trans

cis

1 2 3 4 5b 6b 7b 8b 9b 10b

1 2 3 4a 4a 4a 4a 4b 4c 4d

rt rt rt rt rt 0 −20 0 0 0

58 67 42 60 85 95 73 89 89 92

76:24 76:24 80:20 90:10 90:10 93:7 94:6 93:7 92:8 92:8

69 92 64 96 97 97 97 98 98 99

36 74 29 88 89 89 92 90 92 86

The ee’s were determined after reduction of the products by LiAlH4.

3. CYCLOPROPANATION OF VINYL CARBAMATES The asymmetric cyclopropanation of vinyl carbamates with diazoacetates using chiral ruthenium(salen) and Doyle’s dirhodium catalysts was reported by Nguyen and co-workers.5a The reaction afforded the corresponding protected cyclopropylamine products in good yields but with poor diastereoselectivity and no enantioselectivity. In our study of this reaction, we discovered a highly efficient catalytic system based on the Ru(II)−Pheox 4a catalyst for the asymmetric cyclopropanation of vinylcarbamate derivatives.15 As illustrated in Scheme 4, benzyl vinylcarbamate 11 was readily cyclopropanated at room temperature using only 1 mol % Ru(II)−Pheox 4a catalyst, giving the corresponding protected cyclopropylamine 12 in 99% yield with 70:30 dr and 90% ee. Various diazoacetates 8 were also examined under

a

To Ru(II)−Pheox and 7 was slowly added a solution of 8a in CH2Cl2 over 4 h. bCatalyst at 1 mol % was used.

we found that the carbene transfer reaction catalyzed by Ru(II)−Pheox 4a (R = Ph) proceeded smoothly, giving the corresponding cyclopropane products in high yield and with excellent diastereo- (93:7) and enantioselectivity (97% ee) under mild conditions (Table 1, entry 6). Conversely, using Ru(II)−Pheox 1−3 catalysts with various stereodirecting units (R = i-Pr, t-Bu, and Bn) showed no improvement in yield or stereoselectivity (Table 1, entries 1−3). The highest enantioselectivity was obtained for cyclopropanation using Ru(II)−Pheox 4d, which bears an electron-withdrawing group (Table 1, entry 10). Notably, despite using the sterically 2082


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Accounts of Chemical Research Scheme 4. Cyclopropanation of Vinyl Carbamates

Scheme 5. Preparation of a Key Intermediate in the Synthesis of Belactosin A

4. CYCLOPROPANATION OF α,β-UNSATURATED CARBONYL COMPOUNDS Optically active dicarbonyl cyclopropane compounds are very useful intermediates for the synthesis of various biologically active molecules;17,5a thus, the development of a general and efficient catalytic system for the cyclopropanation of α,βunsaturated carbonyl compounds is highly desirable. Chiral Co(II)- and Rh(II)-based catalysts are the most efficient catalytic systems for the asymmetric cyclopropanation of electron-deficient olefins, as previously reported by Zhang and Davies.7 However, reports of the cyclopropanation of electron-deficient olefins using a ruthenium catalyst are scarce. We developed the Ru(II)−Pheox-catalyzed asymmetric cyclopropanation of α,β-unsaturated carbonyl compounds with ketone- or ester-functionalized diazoacetates.18 The use of methyl (diazoacetoxy)acetate (MDA) 8c as a carbene source for the Ru(II)−Pheox-catalyzed cyclopropanation of ethyl acrylate 14 provided the corresponding dicarbonyl cyclopropane product 15 in 75% yield and with high diastereo- (99:1 dr) and enantioselectivity (96% ee) (Scheme 6). The reaction

the optimal reaction conditions (Scheme 4). Surprisingly, despite the successful use of SDA 8b in the asymmetric cyclopropanation of styrene derivatives, low diastereoselectivity (43:57 dr) and enantioselectivity (49% ee) were obtained in the reaction with benzyl vinyl carbamate. In contrast, excellent enantioselectivity (97% trans ee) was obtained in the cyclopropanation of bulky tert-butyl diazoacetate; however, the diastereoselectivity was low (52:48 dr). Tert-butyl vinyl carbamate was also readily cyclopropanated with diazoacetates to give the desired products in high yields. Notably, the reaction of bulky tert-butyl diazoacetate displayed higher stereoselectivity than that of EDA. Interestingly, higher diastereo- and enantioselectivities were obtained with disubstituted vinyl amines, such as benzyl carbobenzyloxy(vinyl)carbamate and tert-butyl tert-butoxycarbonyl(vinyl)carbamate, compared with those observed in the reactions of monosubstituted vinyl amines. In particular, the highest diastereoand enantioselectivity was achieved for benzyl methyl(vinyl)carbamate (97:3 dr and 99% ee). In addition, our direct enantioselective cyclopropanation of vinyl carbamates was successfully applied to the preparation of a key intermediate in the reported synthesis of belactosin A,16 as shown in Scheme 5. The reduction of optically active cyclopropylamine 12h with DIBAL proceeded smoothly to produce the desired intermediate 2-((tert-butoxycarbonyl)amino) cyclopropylmethanol 13 in 60% yield with excellent enantioselectivity (96% ee). Importantly, the desired configuration at both chiral carbon centers in the cyclopropane motif could be obtained using the (R)-enantiomer of the Ru(II)− Pheox catalyst.

Scheme 6. Cyclopropanation of Ethyl Acrylatea

a

To 4a and 14 was slowly added a solution of diazoacetate in CH2Cl2 over 11 h.

of EDA 8a proceeded with excellent enantioselectivity (99% ee), albeit in low yield (products resulting from the dimerization of the diazo compound were observed). Surprisingly, the cyclopropanation of SDA 8b afforded the corresponding product in only moderate yield (52%) and enantioselectivity (88% ee). 2083


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Scheme 8. Cyclopropanation of Acrylate Derivativesa

The cyclopropanation of various α,β-unsaturated carbonyl compounds, such as α,β-unsaturated esters, ketones, and amides, was also investigated (Scheme 7). The reactions of Scheme 7. Cyclopropanation of α,β-Unsaturated Carbonyl Compounds

a

To 4a and 14 was slowly added a solution of diazoacetate in CH2Cl2 over 4 h.

Scheme 9. Preparation of Key Intermediates in the Synthesis of Bioactive Compounds a

The cyclopropanation of acrylamides was carried out at 40 °C.

nonbulky ethyl and methyl acrylates gave the corresponding bicarbonyl cyclopropane products in higher yield and enantioselectivity compared with bulky phenyl and benzyl acrylates. In contrast, the cyclopropanation of aliphatic and aromatic α,β-unsaturated ketones was more efficient than that of acrylates. α,β-Unsaturated amides were also cyclopropanated by increasing the temperature from room temperature to 40 °C, affording the desired products in high yields (up to 87%) with excellent diastereoselectivity (99:1 dr). However, the higher temperature decreased the enantioselectivity. Surprisingly, the reaction of α-methyl-substituted acrylate and cyclic ester substrates also proceeded smoothly to give the corresponding cyclopropane products in good yields with high diastereo- and enantioselectivities. Nevertheless, the exact mechanism causing the high efficiency of unsaturated carbonyl compounds with this catalytic system remains unclear. Encouraged by these results, we examined the asymmetric cyclopropanation of diethyl (diazomethyl)phosphonate 16 with a series of electron-deficient alkenes 14, as shown in Scheme 8.19 The cyclopropanation of phenyl acrylate afforded cyclopropane 17 in 65% yield with excellent trans-selectivity (99:1 dr) and enantioselectivity (98% ee). In addition, 1-phenylprop2-en-1-one and N-phenylacrylamide were cyclopropanated to provide the corresponding products in high yields with high stereoselectivities. Notably, the reaction yield was sensitive to the acrylamide N-substituent. To demonstrate the utility of this general and highly stereoselective cyclopropanation, 1,2-cyclopropane dicarboxylic acid 18 and 1,2-cyclopropane dimethanol 19, which are key intermediates in the reported synthesis of PTP1B, tcprPNA, and U-106305, were prepared from dicarbonyl cyclopropane 15a (Scheme 9).17a,20,21 The optically active 1,2-cyclopropane dicarboxylic acid intermediate 18 was easily obtained in 85% yield and high diastereoselectivity (99:1 dr) from the hydrolysis of cyclopropane 15a with KOH. On the other hand, the 1,2-

cyclopropane dimethanol intermediate 19 was synthesized in 87% yield with high diastereoselectivity (99:1 dr) by reducing cyclopropane 15a with LiAlH4. The efficient Ru(II)−Pheox-catalyzed asymmetric cyclopropanation of MDA 8c with α,β-unsaturated carbonyl compounds was applied to the enantioselective total synthesis of unique spiral cyclopropane-containing oxindole 22, reported by He and co-workers in 200622 as an HIV-1 non-nucleoside reverse transcriptase inhibitor (Scheme 10). We performed the asymmetric cyclopropanation of 5-bromo-3-methyleneindolin2-one 20 with functionalized diazoacetate MDA 8c, catalyzed by the Ru(II)−Pheox 4a complex under the optimized reaction conditions. As a result, the expected cyclopropane product 21 was obtained in good yield with high diastereoselectivity (93:7 dr) and enantioselectivity (89% ee). The subsequent hydrolysis of cyclopropane 21 readily generated the desired spiral cyclopropane oxindole 22 in 68% yield, while maintaining high diastereoselectivity (93:7 dr) and enantioselectivity (88% ee).

5. CYCLOPROPANATION OF ALLENES The achiral rhodium-catalyzed cyclopropanation of allenes with diazoacetates is commonly employed for the construction of ACPs, but this method often encounters difficulties in controlling the regio- and stereoselectivity of the two adjacent 2084


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and excluding the slow addition of the diazo compound (Table 2, entry 6). Next, we examined a variety of allene derivatives in the asymmetric cyclopropanation of SDA 8b under the optimized reaction conditions (Scheme 11). Monosubstituted aliphatic

Scheme 10. Synthesis of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor

Scheme 11. Cyclopropanation of Various Allenes

carbon−carbon double bonds of the allene. Effective Rh(II)catalyzed cyclopropanation of allenes was reported by Frost6a and Charette,6b and bulky disubstituted diazoacetate was found to be important in providing high regio- and stereocontrol. We described the development of an efficient protocol for the synthesis of optically active alkylidenecyclopropanes via Ru(II)−Pheox-catalyzed asymmetric cyclopropanation of allenes with SDA.23 The cyclopropanation of cyclohexylallene 23 with various diazoacetates 8 was investigated using the Ru(II)−Pheox 4a complex as a catalyst (Table 2). The reaction was found to Table 2. Cyclopropanation of Cyclohexylallenea

Diazoacetate 8b diluted in CH2Cl2 was slowly added over 4 h at −10 °C, and 5 mol % catalyst was used. bCatalyst at 5 mol% was used. rr = regioselectivity ratio. a

allenes cyclopropanated smoothly to give the desired products 24 in moderate to high yields with high regioselectivity and excellent enantioselectivity. However, the diastereoselectivity decreased when less hindered allenes were used as substrates. Disubstituted allenes also readily reacted to generate the corresponding alkylidenecyclopropane products in high yield and high enantioselectivity, albeit with decreased regioselectivity (90:10 rr). This result might have been due to an increase in electron density on the internal carbon−carbon double bond in the allenes and was also observed in the cyclopropanation of aromatic allenes, such as propa-1,2-dien-1-ylbenzene, with the diazo compound added slowly, which proceeded with low regioselectivity (91:9 rr) while maintaining a high yield and excellent diastereoselectivity (99:1) and enantioselectivity (97% ee). In contrast, the reaction of less sterically demanding aromatic allenes provided the corresponding products with high regioselectivity (99:1 rr) and enantioselectivity but reduced diastereoselectivity due to the low steric hindrance. To demonstrate the utility of the products obtained, we developed a highly enantioselective synthesis of cis-cyclopropanes via reduction of chiral alkylidenecyclopropanes. As shown in Scheme 12a, succinimidyl 2-benzylidenecyclopropa-

a

To 4a and 23 was slowly added a solution of diazoacetate in CH2Cl2 over 11 h. bWithout slow addition of the diazo compound.

occur with high regioselectivity, affording the corresponding alkylidenecyclopropane products 24 in high yields and with high stereocontrol. In particular, when SDA 8b was used as the carbene source, the desired product 24 was obtained in 82% yield with excellent diastereoselectivity (97:3 dr) and enantioselectivity (92% ee) (Table 2, entry 4). Moreover, the enantioselectivity of alkylidenecyclopropanes 24 was improved to 96% ee by decreasing the reaction temperature to −10 °C 2085


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systems for highly enantioselective intramolecular cyclopropanation reactions.2 Considering the results achieved for intermolecular cyclopropanation, we next investigated the intramolecular cyclopropanation of a diverse range of trans-allylic diazoacetates using the Ru(II)−Pheox 4a catalyst (Scheme 13).11a The

Scheme 12. Stereoselective Hydrogenation and Nucleophilic Substitution Reaction of Alkylidenecyclopropanes

Scheme 13. Intramolecular Cyclopropanation

necarboxylate 24j was readily hydrogenated with Pd/C and H2 to furnish the corresponding cis-cyclopropane 25 in high yield with excellent cis-selectivity (>99:1) and enantioselectivity (99% ee). In addition, the advantage of using SDA as a carbene source for the cyclopropanation reaction was demonstrated (Scheme 12b). The chiral succinimidyl cyclopropane product 24d easily underwent nucleophilic substitution with benzylamine and benzyl alcohol to form other functionalized alkylidenecyclopropanes (26 and 27) in good yields and with high stereoselectivities. A general overview of our Ru(II)−Pheox-catalyzed cyclopropanation is shown in Figure 3. The rate of cyclopropanation

Ru(II)−Pheox catalyst was found to promote the cyclization of cinnamyl diazoacetate 28 in less than 1 min with high yield (98%) and enantioselectivity (96% ee). In addition, transcinnamyl diazoacetates, with electron-donating and electronwithdrawing substituents in the para position, were cyclopropanated effectively to form the corresponding cyclopropanefused γ-lactones 29 in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Similar results were also obtained in the cyclization of trans-allylic diazoacetate derivatives containing long and short aliphatic chains. Although a few catalytic systems have been developed for the asymmetric intermolecular cyclopropanation of electrondeficient olefins,7 only one example of intramolecular cyclopropanation has been reported, for which both the yield and enantioselectivity were low (32% yield, 80% ee).25 Our successful development of the previously described Ru(II)− Pheox-catalyzed intermolecular cyclopropanation of α,β-unsaturated carbonyl compounds and our continued interest in the asymmetric cyclopropanation of electron-deficient olefins prompted us to explore an intramolecular version of this reaction (Scheme 14).26 As a result, diazoacetates 30 bearing a variety of α,β-unsaturated ester substituents (R1 = MeO, EtO, or BnO) were readily cyclopropanated to afford the corresponding cyclopropane-fused γ-lactones 31 in high yields with excellent enantioselectivity (99% ee). The cyclization of αsubstituted diazoacetates (R2 = Me or Bn) also proceeded smoothly with high yields and enantioselectivities, regardless of the size of the R2 substituent. The enantioselectivity of the catalytic system was significantly improved by carrying out the reaction at 0 °C (from 86% to 94% ee for R1 = BnO, R2 = Me). In addition, diazoacetates bearing α,β-unsaturated amide substituents (R1 = BnNH, Bn(Me)N, or MeO(Me)N) underwent cyclopropanation to give the desired products in high yields with high enantioselectivities.

Figure 3. Comparison of olefinic substrates.

was controlled by electronic factors. Electron-rich styrene and vinyl carbamate derivatives were electronically more favorable than α,β-unsaturated carbonyl compounds due to their greater ability to react with the electrophilic carbenoid intermediate. Hence, the reactivity of the substrate was expected to follow the trend in Figure 3a. In contrast, α,β-unsaturated carbonyl compounds exhibited greater stereocontrol than that of vinyl carbamate and allene substrates (Figure 3b).

6. INTRAMOLECULAR CYCLOPROPANATION Since the first report of catalytic intramolecular cyclization with an unsaturated diazo ketone in 1961,24 considerable efforts have been directed toward the exploration of efficient catalytic 2086


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the desired compound 33 in a 54% yield over two steps, with complete enantioselectivity (99% ee) (Scheme 15, eq 2).

Scheme 14. Cyclopropanation of Electron-Deficient Olefins

7. REUSABLE CHIRAL CATALYSTS Inspired by the high reactivity and enantioselectivity of the Ru(II)−Pheox 4a catalyst, we became interested in designing a Scheme 16. Ru(II)−hm-Pheox-Catalyzed Cyclopropanation

a

The cyclopropanation was carried out at 0 °C.

The synthetic utility of our enantioselective cyclization of α,β-unsaturated carbonyl diazoacetates was demonstrated through the facile preparation of valuable intermediates in the reported synthesis of (2S,1′R,2′R,3′R)-2-(2′,3′dicarboxycyclopropyl)glycine (DCG-IV)3b and dysibetaine CPa27 (Scheme 15). Ring opening of the chiral cycloScheme 15. Preparation of Key Intermediates in the Synthesis of Bioactive Compounds

robust and reusable catalyst that was water-soluble, with water being a desirable solvent for catalysis with respect to environmental concerns, safety, and cost.28 As a result, we developed Ru(II)−hydroxymethyl phenyloxazoline (Ru(II)− hm-Pheox) 5 as an efficient water-soluble catalyst for asymmetric intramolecular cyclopropanation reactions.29 During our ongoing research in this field, we found that the Ru(II)−hm-Pheox complex 5 dissolved in water but not in diethyl ether. When the Ru(II)−hm-Pheox complex 5 was used as a catalyst in the intramolecular cyclopropanation of transcinnamyl diazoacetate 28 in a water/ether biphasic system, the cyclopropane-fused γ-lactone 29a was obtained in 99% yield with 97% ee (Scheme 16). In addition, the water-soluble catalyst Ru(II)−hm-Pheox 5 was verified as reusable by separating the organic phase and adding a new batch of trans-allylic diazoacetate dissolved in ether followed by vigorous stirring for 1−3 h. Interestingly, Ru(II)−hm-Pheox 5 could be reused at least five times without any significant decrease in reactivity or enantioselectivity. The same results were obtained with substrates 28b−d, for which the catalyst could be reused at least 2−3 times (products 29b−d). Notably, although this water-soluble catalytic system was not suitable for the cyclization of trans-allylic diazoacetamides, the reaction of alkenyl diazoketone proceeded smoothly, affording the

propane-fused γ-lactone 31 with triethylamine in methanol and subsequent oxidation with PCC in CH2Cl2 efficiently afforded the desired product 32 with complete enantioselectivity (99% ee) (Scheme 15, eq 1). On the other hand, ring opening of the chiral cyclopropane-fused γ-lactone 31 and subsequent bromination with PPh3/CBr4 in CH2Cl2 afforded 2087


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Accounts of Chemical Research Scheme 17. PS-Ru(II)−Pheox-Catalyzed Cyclopropanationa

storage, the used catalyst showed no loss in catalytic activity or selectivity. The asymmetric cyclopropanation reactions of EDA 8a with styrene and its electron-donating and electron-withdrawing derivatives 7 proceeded in high yields and with excellent transselectivities (up to 94:6 dr) and enantioselectivities (up to 98% ee) (Scheme 17). Impressive results were also obtained for the intermolecular cyclopropanation of various N-vinyl derivatives such as N-vinylpyrrolidone, N-vinylphthalimide, and N-vinylacetamide. In addition, PS-Ru(II)−Pheox 6 proved to be effective in the intermolecular cyclopropanation of sterically demanding vinyl ethers and vinyl acetates, producing the corresponding cyclopropane products in high yields and with excellent enantioselectivities. To demonstrate its reusability, the PS-Ru(II)−Pheox 6 catalyst was isolated from the reaction mixture in the following steps: (i) centrifugation; (ii) washing with n-hexane, diethyl ether, and acetonitrile; and (iii) drying. Surprisingly, PSRu(II)−Pheox 6 could be reused more than 10 times in the intermolecular cyclopropanation of tert-butyl vinyl acetate (Table 3). Moreover, even after three months of storage, the used PS-Ru(II)−Pheox 6 catalyst promoted cyclopropanation without any loss of catalytic activity or enantioselectivity (90% yield and 96% trans ee in most cases).

8. CONCLUSIONS The asymmetric cyclopropanation of diazoacetates with a wide variety of olefins, including vinyl carbamates, allenes, and α,βunsaturated carbonyl compounds, was accomplished with high yields and excellent diastereo- and enantioselectivities using the Ru(II)−Pheox complex as a catalyst. Succinimidyl-, ketone-, and ester-functionalized diazoacetates were found to be efficient carbene sources in the highly stereoselective cyclopropanation of various olefins. In addition, the Ru(II)−Pheox complex was developed into reusable chiral catalysts, namely, water-soluble Ru(II)−hm-Pheox and polymer-supported PS-Ru(II)−Pheox, which could be reused at least five times in inter- and intramolecular cyclopropanation without any loss in catalytic activity or enantioselectivity. Moreover, the Ru(II)−Pheoxcatalyzed asymmetric cyclopropanation reaction proved to be an efficient and straightforward method for the preparation of chiral cyclopropylamines, dicarbonyl cyclopropanes, akylidene cyclopropanes, and cyclopropane-fused γ-lactones, which are important intermediates in the synthesis of many biologically active compounds. We believe that Ru(II)−Pheox catalysts will contribute to the progress of not only asymmetric cyclopropanation but also other asymmetric carbene transfer reactions.

a

To 6 and 7 was slowly added a solution of diazoacetate in CH2Cl2 over 4 h, and the mixture was stirred for an additional 3 h.

corresponding cyclopropane-fused ketone 29e in high yield (89%) with excellent enantioselectivity (98% ee). Furthermore, we also focused on polymer-supported chiral catalysts due to their easy separation from the products and reusability compared with homogeneous catalysts. The development of polymer-supported chiral catalysts for asymmetric synthesis has attracted continuous interest over the past three decades.30 However, to date, relatively low to moderate yields have been achieved in asymmetric cyclopropanation promoted by polymer-supported chiral catalysts.31 Inspired by these observations, we developed a macroporous polymersupported chiral PS-Ru(II)−Pheox complex 6 and disclosed its high reactivity, stereoselectivity, and reusability in the asymmetric cyclopropanation of diazoacetates.11a Even after Table 3. Reusability of the PS-Ru(II)−Pheox Catalyst

a

cycle

1

2

3

4

5

6

7

8

9

10

11a

trans ee (%) cis ee (%) yield (%)

96 86 90

96 85 90

96 86 90

96 86 90

96 86 91

96 86 91

96 85 90

96 86 90

96 86 90

95 84 90

96 85 90

The PS-Ru(II)−Pheox 6 catalyst used previously 10 times was then reused after three months of storage. 2088


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(6) (a) Gregg, T. M.; Farrugia, M. K.; Frost, J. R. Rhodium-Mediated Enantioselective Cyclopropanation of Allenes. Org. Lett. 2009, 11, 4434−4436. (b) Lindsay, V. N. G.; Fiset, D.; Gritsch, P. J.; Azzi, S.; Charette, A. B. Stereoselective Rh2(S-IBAZ)4-Catalyzed Cyclopropanation of Alkenes, Alkynes, and Allenes: Asymmetric Synthesis of Diacceptor Cyclopropylphosphonates and Alkylidenecyclopropanes. J. Am. Chem. Soc. 2013, 135, 1463−1470. (7) (a) Chen, Y.; Ruppel, J. V.; Zhang, X. P. Cobalt-Catalyzed Asymmetric Cyclopropanation of Electron-Deficient Olefins. J. Am. Chem. Soc. 2007, 129, 12074−12075. (b) Wang, H.; Guptill, D. M.; Varela-Alvarez, A.; Musaev, D. G.; Davies, H. M. L. RhodiumCatalyzed Enantioselective Cyclopropanation of Electron-Deficient Alkenes. Chem. Sci. 2013, 4, 2844−2850. (8) (a) Zhang, Z.; Wang, J. Recent Studies on the Reaction of αDiazocarbonyl Compounds. Tetrahedron 2008, 64, 6577−6605. (b) Kornecki, K. P.; Briones, J. F.; Boyarskikh, V.; Fullilove, F.; Autschbach, J.; Schrote, K. E.; Lancaster, K. M.; Davies, H. M. L.; Berry, J. F. Direct Spectroscopic Characterization of a Transitory Dirhodium Donor-Acceptor Carbene Complex. Science 2013, 342, 351−354. (9) Dörwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1999. (10) (a) Doyle, M. P. Catalytic Methods for Metal Carbene Transformations. Chem. Rev. 1986, 86, 919−939. (b) Davies, H. M. L.; Antoulinakis, E. G. Intermolecular Metal-Catalyzed Carbenoid Cyclopropanations. Org. React. 2001, 57, 1−326. (11) (a) Abu-Elfotoh, A.-M.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Asymmetric Inter- and Intramolecular Cyclopropanation Reactions Catalyzed by a Reusable Macroporous-Polymer-Supported Chiral Ruthenium(II)/Phenyloxazoline Complex. Angew. Chem., Int. Ed. 2010, 49, 8439−8443. (b) Chanthamath, S.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Highly Stereoselective Ru(II)-Pheox Catalyzed Asymmetric Cyclopropanation of Terminal Olefins with Succinimidyl Diazoacetate. Chem. Commun. 2012, 48, 7750−7752. (c) Nishiyama, H.; Soeda, N.; Naito, T.; Motoyama, Y. Single-Chiral Bis(Oxazolinyl)pyridine (pybox). Efficiency in Asymmetric Catalytic Cyclopropanation. Tetrahedron: Asymmetry 1998, 9, 2865−2869. (d) The study of computational chemical analysis for the transition state is ongoing: Computational Chemical Analysis for Ru(II)−Pheox Catalyzed Stereoselective Cyclopropanation, unpublished manuscript. (12) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. New Chiral Ruthenium Bis(oxazolinyl)pyridine Catalyst. Efficient Asymmetric Cyclopropanation of Olefins with Diazoacetates. J. Am. Chem. Soc. 1994, 116, 2223−2224. (13) (a) Brunel, J. M.; Legrand, O.; Reymond, S.; Buono, G. First Iminodiazaphospholidines with a Stereogenic Phosphorus Center. Application to Asymmetric Copper-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 1999, 121, 5807−5808. (b) Munslow, I. J.; Gillespie, K. M.; Deeth, R. J.; Scott, P. Bidentate Carbenoid Ester Coordination in Ruthenium(II) Schiff-Base Complexes Leading to Excellent Levels of Diastereo- and Enantioselectivity in Catalytic Alkene Cyclopropanation. Chem. Commun. 2001, 1638−1639. (c) Chan, K.-H.; Guan, X.; Lo, V. K.-Y.; Che, C.-M. Elevated Catalytic Activity of Ruthenium(II)-Porphyrin-Catalyzed Carbene/Nitrene Transfer and Insertion Reactions with N-Heterocyclic Carbene Ligands. Angew. Chem., Int. Ed. 2014, 53, 2982−2987. (14) Ruppel, J. V.; Gauthier, T. J.; Snyder, N. L.; Perman, J. A.; Zhang, X. P. Asymmetric Co(II)-Catalyzed Cyclopropanation with Succinimidyl Diazoacetate: General Synthesis of Chiral Cyclopropyl Carboxamides. Org. Lett. 2009, 11, 2273−2276. (15) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S. Highly Enantioselective Synthesis of Cyclopropylamine Derivatives via Ru(II)-Pheox-Catalyzed Direct Asymmetric Cyclopropanation of Vinylcarbamates. Org. Lett. 2013, 15, 772−775. (16) (a) Brandl, M.; Kozhushkov, S. I.; Loscha, K.; Kokoreva, O. V.; Yufit, D. S.; Howard, J. A. K.; de Meijere, A. Synthesis of trans-(2Aminocyclopropyl)alanine - A Key Constituent of the Novel Antitumor Antibiotic Belactosin A. Synlett 2000, 1741−1744. (b) Armstrong, A.; Scutt, J. N. Stereocontrolled Synthesis of 3-

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Funding

This work was supported by a Grant-in-Aid for Scientific Research (B) (No. 26288087) from the Japan Society for the Promotion of Science. Notes

The authors declare no competing financial interest. Biographies Soda Chanthamath received his Ph.D. in Functional Material Engineering under the supervision of Prof. Seiji Iwasa at the Graduate School of Engineering, Toyohashi University of Technology, in 2013. After postdoctoral research in the Department of Environmental and Life Sciences, he joined the Life Environmental Engineers Education Project at the same university as an assistant professor in 2014. His research interests focus on asymmetric carbene transfer reactions and the synthesis of biologically active compounds. Seiji Iwasa obtained his Doctor of Engineering degree in 1991 from Chiba University. He then joined Professor V. H. Rawal’s group at The Ohio State University in 1991 and later moved to The University of Chicago as a postdoctoral researcher. He returned to Japan in 1995 and jointed Prof. Ryoji Noyori’s ERATO research group and later became a professor at the Toyohashi University of Technology. His group works in three main areas: (1) asymmetric catalysis, (2) natural product chemistry, and (3) immunoassay and molecular sensors (for additional details, see Iwasa Lab: http://www.siorgchem.ens.tut.ac.jp).

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Enantioselective Cyclopropanation of a Wide Variety of Olefins

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