Direct Sulfide-Catalyzed Enantioselective Cyclopropanations of

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Direct Sulfide-Catalyzed Enantioselective Cyclopropanations of Electron-Deficient Dienes and Bromides Qing-Zhu Li,† Xiang Zhang,†,‡ Rong Zeng,† Qing-Song Dai,† Yue Liu,† Xu-Dong Shen,† Hai-Jun Leng,† Kai-Chuan Yang,† and Jun-Long Li*,†,‡ †

Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China ‡ Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China S Supporting Information *

ABSTRACT: A catalytic highly regioselective, diastereoselective, and enantioselective cyclopropanation of electron-deficient dienes and bromides via direct sulfide organocatalysis is reported. A variety of vinylcyclopropanes featuring a quaternary chiral center were synthesized in up to 99% yield and up to 98:2 enantiomeric ratio (er). These products could be facilely transformed to various interesting molecules with great structural diversity.

S

Scheme 1. Strategies for the Stereoselective Reactions Catalyzed by Chiral Sulfides

ince the pioneering work of Johnson, Coery, and Chaykovsky in the 1960s, synthetic applications of sulfur ylides in cyclization reactions have achieved significant success in academia.1 Various elegant methodologies have been developed, opening new avenues for the assembly of diverse cyclic structural motifs.2 However, the majority of these examples have been developed based on the use of stoichiometric sulfur ylides, which required advanced preparation of ylide reagents and inevitably discharged a large amount of sulfide byproducts.1f Because of the urgent demand for an “ideal synthesis”, in terms of step-economy, atom-economy, and environmental compatibility, 3 the development of asymmetric sulfide catalysis, including indirect catalytic pathways (see Scheme 1a) and direct sulfide organocatalysis (see Scheme 1b), has attracted broad attention among synthetic chemists.4 Although remarkable progress has been achieved over decades of research, the potentially more-efficient direct sulfide catalysis has remained underdeveloped. Such catalysis was only applied to a few types of asymmetric transformations, such as aldehyde epoxidations and aldimine aziridinations.4c−i Moreover, currently established catalytic reactions typically require harsh conditions (i.e., strong base and low temperature), have narrow substrate scopes (limited to semistable and highly reactive sulfur ylides),5 and sulfide availability issues (multistep synthesis needed and lack of the other sulfide enantiomer). In particular, and to the best of our knowledge, the halide substrates with an electron-withdrawing group have never been utilized in sulfide catalyzed asymmetric reactions thus far. Therefore, it is highly desirable to explore new methodologies that not only expand the application scope of sulfide catalysis, but also address the above existing drawbacks in this field. Cyclopropanation is one of the most important synthetic applications of ylide chemistry, which provides facile access to various three-membered carbocycles.6 However, reports on © XXXX American Chemical Society

catalytic-ylide-based enantioselective cyclopropanation are quite limited. An elegant pioneering work by Aggarwal et al. demonstrated that chiral sulfides could catalyze metal carbenes, Received: May 15, 2018

A

DOI: 10.1021/acs.orglett.8b01537 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters formed in situ, to undergo asymmetric cyclopropanation.7a Tang and co-workers employed sulfur ylides as catalysts to promote the [1 + 2] annulation.7b However, both of these reactions proceed based on a strategy of indirect sulfide catalysis, and only highly reactive, semistable sulfur ylide intermediates were involved (see Scheme 1a). The first direct organocatalytic asymmetric ylide-based cyclopropanation was achieved by the group of Gaunt, where ammonium ylides were used as key intermediates.8 Herein, we report an unprecedented highly stereoselective cyclopropanation of electron-deficient dienes and bromides via direct sulfide organocatalysis.9 The use of malononitrile as a traceless mask to activate the enone substrates, as well as stabilize the enolate intermediate for limiting proton transfer and decreasing the erosion of enantioselectivity is key to the success of this asymmetric catalytic approach2j (see Scheme 2); moreover, such a

Table 1. Optimization of Sulfide-Catalyzed Cyclopropanationa

Scheme 2. Stable-Ylide-Based Asymmetric Cyclopropanation via Direct Sulfide Organocatalysis

entry

3

solvent

t (h)

yieldc (%)

enantiomeric ratio, erd

1 2 3e 4 5 6 7 8 9 10f 11 12 13g 14

3a 3a 3a 3b 3c 3d 3e 3f 3g 3g 3h 3i 3i 3j

MeCN CHCl3 toluene MeCN MeCN MeCN MeCN MeCN MeCN DCM MeCN MeCN MeCN MeCN

24 48 48 48 72 72 48 48 24 24 72 48 48 48

85 42 35 51 12 28 62 75 85 90 18 42 95 72

81:19 78:22 76:24 53:47 54:46 55:45 67:33 72:28 24:76 15:85 54:46 95:5 96:4 79:21

a Reactions were performed with diene 1a (0.12 mmol), bromide 2a (0.1 mmol), sulfide 3 (0.02 mmol), and NaHCO3 (0.12 mmol) in 1.0 mL of solvent. bDetermined by crude 1H NMR analysis. cIsolated yield. dDetermined by chiral HPLC analysis. eAt 50 °C. f20 mg of 4 Å MS was added. gConcentration was increased to 2 M using 0.05 mL of solvent.

malonontrile moiety could also be used as a valuable electron-withdrawing functional group in further synthetic derivations.10 Notably, this process works under mild reaction conditions, is compatible with less-reactive sulfur ylides, and uses a commercially available, inexpensive sulfide catalyst. We started by investigating the reaction of electron-deficient diene 1a and 2-bromoacetophenone 2a in the presence of various chiral sulfides 3 at ambient temperature (see Table 1). To our satisfaction, the combination of 3a and a weak base NaHCO3 afforded the desired vinylcyclopropane (VCP)11 4a in remarkable yield and diastereoselectivity, albeit with moderate enantioselectivity (Table 1, entry 1). Screening of solvents and bases led to inferior results in terms of reaction efficiency and enantioselectivity (entries 2 and 3 in Table 1 and data in the Supporting Information (SI)). An increase of steric hindrance of the camphor-derived-sulfide catalysts also failed to improve the reaction outcome (entries 4−8 in Table 1). Notably, sulfide 3g with a free hydroxyl group could reverse the enantioselectivity, and the corresponding enantiomer of 4a was obtained in excellent yield (entries 9 and 10 in Table 1; for more data and related discussion, see the SI).12 However, the more rigid sulfide 3h showed poor reactivity and quite disappointing stereocontrol ability (Table 1, entry 11). To our satisfaction, the commercially available, inexpensive isothiocineole 3i, which was developed by Aggarwal and coworkers,13 delivered 4a with a dramatic improvement of the enantioselective ratio (Table 1, entry 12). Further increases of the reaction concentration led to satisfactory yield without loss of stereoselectivity (Table 1, entry 13). The axial chiral sulfide 3j also proved to be an effective catalyst for promoting this

cyclopropanation, whereas the enantioselectivity was moderate (Table 1, entry 14). With the optimal conditions in hand, we set out to explore the generality of this catalytic system. As shown in Table 2, a range of dienes 1 with various substituted β-aryl groups could be well-tolerated, affording the multifunctionalized VCPs 4a−4i in satisfying yields and outstanding enantioselectivity (entries 1−9 in Table 2). Heteroaryl- or naphthyl-containing products were also obtained with high levels of enantiopurity (Table 2, entries 10−12). Moreover, different carboxylates, including methyl- and tert-butyl-esters were also tested, and they barely affected the reaction (entries 13 and 14 in Table 2). On the other hand, various aryl-containing α-bromoketones 2 were explored: a wide range of ortho-, meta-, and para-substituents of different electronic properties were well-tolerated to produce 4o−4w in uniformly excellent enantioselectivity (entries 15−23 in Table 2); as expected, ketones with a heteroaryl substituent or naphthyl substituent were suitable substrates, delivering the corresponding chiral products in 76%−94% yields (entries 24 and 25 in Table 2). Gratifyingly, alkyl-substituted ketones such as α-bromoacetone could participate in the catalytic reaction and offered the desired 4z in good yield and stereoselectivity (Table 2, entry 26). To test the robustness and utility of this catalytic method in preparative synthesis, a large-scale reaction was performed and B

DOI: 10.1021/acs.orglett.8b01537 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Scope of the Asymmetric Cyclopropanation of Dienes 1 and α-Bromoketones 2a

entry b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 a

R1

R2

R3

yield (%)

enantiomeric ratio, er

H 3-BrC6H4 3-ClC6H4 4-FC6H4 4-ClC6H4 3-MeC6H4 3-MeOC6H4 4-MeC6H4 4-MeOC6H4 2-furyl 2-thienyl 2-naphthyl H H H H H H H H H H H H H H

Et Et Et Et Et Et Et Et Et Et Et Et Me t-Bu Et Et Et Et Et Et Et Et Et Et Et Et

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeOC6H4 4-MeC6H4 2-MeC6H4 4-NO2C6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 3-BrC6H4 3,4-di-ClC6H4 2-thienyl 2-naphthyl Me

4a, 95 4b, 78 4c, 92 4d, 90 4e, 84 4f, 78 4g, 65 4h, 78 4i, 95 4j, 66 4k, 80 4l, 99 4m, 89 4n, 85 4o, 62 4p, 75 4q, 94 4r, 95 4s, 63 4t, 71 4u, 64 4v, 93 4w, 87 4x, 76 4y, 94 4z, 71

96:4 96:4 95:5 95:5 95:5 96:4 95:5 95:5 96:4 95:5 96:4 95:5 96:4 96:4 95:5 96:4 95:5 95:5 94:6 96:4 96:4 94:6 98:2 95:5 93:7 94:6

See Table 1, as well as the SI, for detailed procedure. bThe absolute configuration of 4a was determined by X-ray diffraction (XRD) analysis.

1.77 g of the enantioenriched 4a were obtained (see Scheme 3a). Subsequently, the versatility of the VCP product was also investigated. As shown in Scheme 3b, 4a could be transformed to the multisubstituted aniline 5 with Pd(PPh3)4 as a catalyst.14 Importantly, the malononitrile moiety was easily hydrolyzed under mild conditions, delivering the 1,4-diketone 6 in excellent yield, while retaining the stereochemical information. Such diketone compounds could undergo further intramolecular cyclization in the presence of hydrazine hydrate to generate the fused bicyclic molecule 7 in good yield, albeit with a slight loss of enantiopurity.15 In addition, modifying the carboxyl group of 6 provided access to a valuable cyclic tertiary chloride 8 via a sequential alkaline hydrolysis and decarboxylative chlorination process.16 These products with structural diversity might be potentially useful in medicinal chemistry.17 Next, we turned our attention to the evaluation of bromides with other types of electron-withdrawing groups in the catalytic asymmetric cyclopropanation. Rewardingly, the α-brominated ester or amide substrate both delivered the desired VCPs 9a and 9b in high yields (84%−92%) with moderate to good stereoselectivity, respectively. A less electron-deficient 2,4dinitrobenzyl bromide was also a suitable reaction partner, offering the corresponding 9c in satisfying yield and enantioselectivity, albeit with low diastereoselectivity (4:1 dr). Moreover, the medicinally interesting chromone scaffold could be directly incorporated into the bromide substrate to generate the structurally complex 9d in reasonable yield and stereo-

Scheme 3. Practical Preparation and Synthetic Transformation of the Chiral VCP 4a

selectivity, thereby reflecting the power of this catalytic process (Scheme 4). C

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Organic Letters

variety of optically active vinylcyclopropanes were synthesized from readily available starting materials under mild conditions. These products could be further transformed to a range of interesting molecules with great structural diversity. Based on the new compounds, related biological studies are currently underway in our laboratory, and the results will be reported in due course.

Scheme 4. Sulfide-Catalyzed Asymmetric Cyclopropanations of Bromides with Other Electron-Withdrawing-Groups

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01537. Complete experimental procedures, characterization of new products, NMR spectra, and HPLC chromatograms (PDF)

The potential of this sulfide catalysis was further explored using 1,3-dibromoacetone 10 as a substrate. Interestingly, the monocyclopropane 11 and biscyclopropane 12 were selectively synthesized by simply controlling the ratio of 1a and 10 in the reaction system, furnishing high yields and excellent levels of stereoselectivity in both cases. Of note, direct organocatalytic dicyclopropanation remains challenging and has rarely been reported previously.6a,18 Hydrolysis of 12 gave a C2-symmatric triketocylopropane 13 in remarkable yield (see Scheme 5a).

Accession Codes

CCDC 1589219, 1589309, and 1814222 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

Scheme 5. Asymmetric Cyclopropanation of 1,3Dibromoacetone and Further Synthetic Derivatization

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun-Long Li: 0000-0002-4700-0142 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the NSFC (Nos. 21702021, 21502009, and 81703809), the Science & Technology Department of Sichuan Province (No. 2017JQ0032), the “Thousand Talents Program” of Sichuan Province, the “Chengdu Talents Program”, Chengdu Industrial Collaborative Innovation Project (No. 2016-XT00-00023-GX) and the Start-up Fund of Chengdu University.

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