Asymmetric Synthesis of α-Fluoro-β-Amino-oxindoles with

Letter pubs.acs.org/OrgLett

Asymmetric Synthesis of α‑Fluoro-β-Amino-oxindoles with Tetrasubstituted C−F Stereogenic Centers via Cooperative CationBinding Catalysis Sushovan Paladhi,† Sang Yeon Park,† Jung Woon Yang,‡ and Choong Eui Song*,† †

Department of Chemistry, Sungkyunkwan University, Suwon, 440-746, Korea Department of Energy Science, Sungkyunkwan University, Suwon, 440-746, Korea

‡

S Supporting Information *

ABSTRACT: Biologically relevant chiral 3,3-disubstituted oxindole products containing a β-fluoroamine unit are obtained in high yields and with excellent stereoselectivity (up to 99% ee, dr >20:1 for syn) through the organocatalytic direct Mannich reaction of 3-fluoro-oxindoles as fluoroenolate precursors and α-amidosulfones as the bench-stable precursors of sensitive imines by using a chiral oligoethylene glycol and KF as a cation-binding catalyst and base, respectively. This protocol can be easily scaled without compromising the asymmetric induction. Furthermore, this protocol was also successfully extended to generate tetrasubstituted C−Cl and C−Br stereogenic centers.

T

reacting anion.”8 Recently, we successfully addressed this limitation of chiral crown ethers as cation-binding catalysts by employing Song’s chiral oligoEGs such as 110 as an evolved cation-binding catalyst (Figure 2a), in which the ether oxygens act as the Lewis base to coordinate with metal ions such as K+, thus generating a soluble chiral anion in a confined chiral space. Moreover, the terminal phenolic groups are capable of simultaneously activating the electrophile by hydrogen bonding interaction, resulting in a well-organized transition state leading to excellent stereoinduction. This concept for the ambiphilic activation using Song’s chiral oligoEGs as an evolved cationbinding catalytic system has been successfully applied to some challenging catalytic asymmetric reactions.10 We believe that this evolved cation-binding catalyst system is ideally suited for the asymmetric Mannich reaction of 3-fluoroindoles 2 and αamidosulfones 3,11 in which potassium fluoride (KF), upon activation by the chiral cation-binding catalyst, generates the corresponding imine substrate in situ from α-amidosulfones as well as the fluoroenolate substrate in situ from oxindoles.12 Subsequently, the catalyst would bring both the activated reacting partners in a close proximity, thus enhancing the reactivity and efficiently transferring the stereochemical information (Figure 2b). To prove our assumption, 3-fluoro-N-methy-2-oxindole (2a) and 4-fluorophenyl-α-amidosulphone (3a) were chosen as the model substrates. After a quick survey of the reaction parameters (Table 1), an optimized reaction system consisting of 2a (1 equiv), amidosulfone 3a (1.5 equiv) in the presence of

he synthesis of chiral oxindole scaffolds, especially chiral 3,3′-disubstituted oxindoles, is of particular importance for their structurally determining presence in various natural products, and biologically and pharmaceutically relevant compounds.1,2 For example, various 3,3′-substituted oxindoles bearing a β-aminocarbonyl unit are found in the skeletons of some natural products having interesting biological properties (Figure 1a).1e,3 Chiral oxindoles containing a tetrasubstituted C−F stereogenic center at the 3-position are also found in many pharmaceutically relevant compounds and drug candidates (Figure 1b).4,5 Notably, the molecules containing βfluoroamine moieties have recently received great interest in medicinal chemistry owing to their privileged structural motif.6 The presence of fluorine at the β-position is well-known to lower the pKa of neighboring amines, thus enhancing binding interactions and improving metabolic stability. This leads to increased penetration through the central nervous system of a biological system.7 Given the importance of chiral oxindole compounds and chiral β-fluoroamine compounds in medicinal chemistry, chiral oxindole derivatives containing a β-fluoroamine unit are expected to have very interesting pharmaceutical properties, and as a consequence, developing a new method for the synthesis of this type of compounds is highly desirable. The concept of asymmetric cation-binding catalysis is to generate reactive “chiral” anions (nucleophiles) from achiral salts by binding to their counter cations with a catalyst in the “chiral cage” of a catalyst.8,9 Although “the conceptual validity of cation-binding catalysis using chiral crown ethers has been demonstrated,” as stated by Jacobsen, “the scope of this approach to catalysis has far been limited, because of the dif f iculty associated with creating a highly organized chiral environment around a © 2017 American Chemical Society

Received: August 24, 2017 Published: September 27, 2017 5336

DOI: 10.1021/acs.orglett.7b02628 Org. Lett. 2017, 19, 5336−5339

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

entry

solvent

conversion (%)b

drb

ee (%)c

1 2d 3e 4 5 6 7 8

o-xylene o-xylene o-xylene m-xylene toluene CH2Cl2 1,4-dioxane acetonitrile

>99 >99 92 >99 >99 82 74 >99

>20:1 >20:1 >20:1 >20:1 >20:1 10:1 10:1 9:1

94 94 90 93 90 93 32 11

a

Unless otherwise indicated, the reactions were performed with 2a (0.1 mmol), (R)-1 catalyst (10 mol %), KF (0.3 mmol), and αamidosulfone 3a (0.15 mmol) in the indicated solvent (0.5 mL) for 60 h at room temperature. bConversion and diastereomeric ratio (dr) were determined by 1H NMR analysis of the unpurified reaction mixture. cEnantiomeric excess (ee) was determined by HPLC analysis using a chiral stationary phase. dThe reaction was carried out on a 10 mmol scale (for 2a). eThe reaction was carried out in 0.1 M condition.

Other nonpolar solvents such as m-xylene, toluene, and CH2Cl2 also provided excellent yields and enantioselectivities (entries 4−6). However, polar solvents such as 1,4-dioxane and acetonitrile proved to be worse in terms of reaction rates and enantioselectivities (entries 7 and 8). Furthermore, the generality of our catalytic protocol was evaluated. As shown from the results in Scheme 1, our catalytic conditions were found to be general with α-amidosulfones 3 bearing different aryl and heteroaryl substituents. Regardless of the electronic and steric nature of the substituents on the aromatic ring, α-amidosulfones 3a−3k smoothly converted to the corresponding Mannich adducts 4aa−4fn in moderate to high yields and excellent diastereo- and enantioselectivity. Heteroaromatic substrates, 3m−3p, such as furanyl and thienyl also afforded excellent yields and stereoselectivities. In addition, aliphatic substrates such as alkyl α-amidosulfone 3q were also explored for this reaction; however, they did not react under the same conditions. Gratifyingly, this reaction was also found to be general with diverse 3-fluoro-oxindoles 2 as the Mannich donors (Scheme 2). The stereoselectivity was independent of the electronic and steric nature of the indole ring (Scheme 2). In all the cases, high ee’s (83−99% ee) were achieved under the optimized catalytic conditions. The relative and absolute configurations were determined to be “syn” and (S, S) by the single crystal X-ray crystallographic analysis of the compound 4bc.13 By analogy, the same configuration was assigned to all the compounds 4. Finally, the present catalytic conditions were successfully extended for the synthesis of other halogenated oxindoles such as 6ac and 8ac containing tetrasubstituted C−Cl and C−Br stereogenic centers, respectively.14,15 As shown in Scheme 3, the direct Mannich reactions of oxindoles 5a and 7a afforded the Mannich products 6ac and 8ac with excellent stereoselectivity (up to 98% ee, dr >20:1). The reaction with N-Boc protected 3-fluoro-2-oxindole as the substrate proceeded smoothly to afford the corresponding product. But only moderate stereoselectivity was obtained (see Supporting Information for more details).

Figure 1. (a) Some natural compounds containing β-amino-2-oxindole unit. (b) Bioactive compounds containing a 3-fluoro-oxindole unit.

Figure 2. (a) Song’s oligoEG catalyst. (b) Proposed asymmetric Mannich reaction of 3-fluoroindoles 2 and α-amido sulfones 3 catalyzed by Song’s chiral oligoEG 1.

catalyst (R)-1 (10 mol %) and KF (3 equiv) as the base in oxylene (0.2 M) at room temperature was obtained, affording the desired Mannich product 4aa with excellent stereoselectivity (94% ee, dr >20:1) (entry 1). The current reaction could be easily scaled up to 10 mmol (for 2a) without compromising the asymmetric induction (entry 2). Dilution of the reaction mixture turned out to be detrimental (entry 3). 5337

DOI: 10.1021/acs.orglett.7b02628 Org. Lett. 2017, 19, 5336−5339

Letter

Organic Letters Scheme 1. Substrate Scope of the Mannich Reaction of 2a to α-Amidosulfone 3a

Scheme 2. Substrate Scope for the Mannich Reaction of 2 to α-Amidosulfone 3c, 3m, and 3na

a

Unless otherwise indicated, the reactions were performed with 2 (0.1 mmol), 3c/3m/3n (0.15 mmol), KF (0.3 mmol), and (R)-1 (10 mol %) in o-xylene (0.5 mL) at room temperature for 60 h.

Scheme 3. Mannich Reaction of 5a or 7a to α-Amidosulfone 3ca a Unless otherwise indicated, reactions were performed with 2a (0.1 mmol), 3 (0.15 mmol), KF (0.3 mmol), and (R)-1 (10 mol %) in oxylene (0.5 mL) at room temperature for 60 h.

In summary, the concept of cooperative cation-binding catalysis was successfully applied for the synthesis of biologically relevant chiral α-fluoro-β-amino-oxindole derivatives with tetrasubstituted C−F stereogenic centers. Direct organocatalytic Mannich reactions with 3-fluorooxindoles as the Mannich donors and α-amidosulfones as the bench-stable imine precursors by using Song’s chiral cation-binding catalyst and KF as the base at room temperature afforded highly enantio- and diastereoenriched chiral α-fluoro-β-amino-oxindoles (up to 99% ee and dr >20:1 (syn:anti), expected to have very interesting biological and pharmaceutical properties. This protocol was also successfully extended to generate tetrasubstituted C−Cl and C−Br stereogenic centers. The cationbinding catalysis in a densely confined chiral cage in situ formed by the incorporation of the potassium salt is the key to this successful catalysis. Like enzymes, catalytic sites of (R)-1

a

Unless otherwise indicated, the reactions were performed with 2 (0.1 mmol), 3c (0.15 mmol), KF (0.3 mmol), and (R)-1 (10 mol %) in oxylene (0.5 mL) at room temperature for 60 h.

simultaneously activate both the reacting partners (imine and fluoroenolate) and keep them in close proximity, thus enhancing the reactivity and efficiently transferring the stereochemical information.10 Further applications of our cooperative cation-binding catalysis concept for the discovery 5338

DOI: 10.1021/acs.orglett.7b02628 Org. Lett. 2017, 19, 5336−5339

Letter

Organic Letters

(7) (a) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. ChemMedChem 2007, 2, 1100. (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (8) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534. (9) Oliveira, M. T.; Lee, J.-W. ChemCatChem 2017, 9, 377. (10) For recent reports, see: (a) Yan, H.; Jang, H. B.; Lee, J. W.; Kim, H. K.; Lee, S.; Yang, J. W.; Song, C. E. Angew. Chem., Int. Ed. 2010, 49, 8915. (b) Yan, H.; Oh, J. S.; Lee, J. W.; Song, C. E. Nat. Commun. 2012, 3, 1212. (c) Park, S. Y.; Lee, J. W.; Song, C. E. Nat. Commun. 2015, 6, 7512. (d) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Angew. Chem., Int. Ed. 2016, 55, 331. (e) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2016, 138, 16486. (f) Vaithiyanathan, V.; Kim, M. J.; Liu, Y.; Yan, H.; Song, C. E. Chem. - Eur. J. 2017, 23, 1268. (g) Kim, M. J.; Xue, L.; Liu, Y.; Paladhi, S.; Park, S. J.; Yan, H.; Song, C. E. Adv. Synth. Catal. 2017, 359, 811. (h) Yu, L.; Wu, X.; Kim, M. J.; Vaithiyanathan, V.; Liu, Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Adv. Synth. Catal. 2017, 359, 1879. (i) Park, S. Y.; Hwang, I. S.; Lee, H. J.; Song, C. E. Nat. Commun. 2017, 8, 14877. (j) Tan, Y.; Luo, S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2017, 139, 6431. (k) Paladhi, S.; Liu, Y.; Kumar, B. S.; Jung, M. J.; Park, S. Y.; Yan, H.; Song, C. E. Org. Lett. 2017, 19, 3279. (l) Park, S. Y.; Liu, Y.; Oh, J. S.; Kweon, Y. K.; Jeong, Y. B.; Tan, Y.; Lee, J.-W.; Yan, H.; Song, C. E. Chem. - Eur. J. 2017, 23, DOI: 10.1002/chem.201703800. (11) For recent selected literature on the asymmetric Mannich reaction of 3-substituted oxindole derivatives, see: (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583. (b) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2009, 74, 4650. (c) Shimizu, S.; Tsubogo, T.; Xu, P.; Kobayashi, S. Org. Lett. 2015, 17, 2006. (d) Torii, M.; Kato, K.; Uraguchi, D.; Ooi, T. Beilstein J. Org. Chem. 2016, 12, 2099. (e) Chen, X.; Li, Y.; Zhao, J.; Zheng, B.; Lu, Q.; Ren, X. Adv. Synth. Catal. 2017, 359, 3057. (12) For selected literature on bench-stable imine surrogates, see: (a) α-Amidosulfones: Petrini, M. Chem. Rev. 2005, 105, 3949. (b) N,N-acetals: Kano, T.; Yurino, T.; Asakawa, D.; Maruoka, K. Angew. Chem., Int. Ed. 2013, 52, 5532. (c) N,O-acetals: Wang, Y.; Jiang, L.; Li, L.; Dai, J.; Xiong, D.; Shao, Z. Angew. Chem., Int. Ed. 2016, 55, 15142. (13) CCDC 1554384 contains the supplementary crystallographic data for the compound 4bc. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif. (14) Noole, A.; Järving, I.; Werner, F.; Lopp, M.; Malkov, A.; Kanger, T. Org. Lett. 2012, 14, 4922. (15) Li, J.; Du, T.; Zhang, G.; Peng, Y. Chem. Commun. 2013, 49, 1330.

of new and challenging organic transformations are currently underway in our laboratory.

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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.7b02628. Experimental details, analytical data (PDF) Crystallographic data for 4bc (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jung Woon Yang: 0000-0001-8636-0901 Choong Eui Song: 0000-0001-9221-6789 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the Ministry of Science, ICT, and Future Planning in Korea (Grant Nos. NRF2014R1A2A1A01005794 and NRF-2016R1A4A1011451).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b02628 Org. Lett. 2017, 19, 5336−5339