Enantioselective Construction of CF3-Containing Spirooxindole γ

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Enantioselective Construction of CF3‑Containing Spirooxindole γ‑Lactones via Organocatalytic Asymmetric Michael/Lactonization Zhong-Tao Yang, Jianhong Zhao,* Wu-Lin Yang, and Wei-Ping Deng* School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China

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S Supporting Information *

ABSTRACT: A highly enantioselective Michael/lactonization cascade reaction of 3-hydroxyoxindoles with 3-trifluoroethylidene oxindoles was developed. The use of a cinchona-derived squaramide catalyst is essential in achieving high diastereo- and enantioselectivities. This reaction represents the first example of intramolecular amide C−N bond cleavage and lactonization of 3-hydroxyoxindoles with 3-trifluoroethylidene oxindoles, which provides an efficient and convenient approach to diverse CF3containing spirooxindole γ-lactones in high yields and good to excellent diastereo- and enantioselectivities. Scheme 1. Access to Enantioenriched Spirooxindole γLactones from 3-Hydroxyindoles

C

hiral spirooxindole has emerged as a fascinating scaffold that defines the typical structural core of many nature products and pharmaceuticals.1 As an important subset of spirooxindole-based molecules, spirooxindole lactones have become attractive synthetic targets because they possess a wide range of biological activities, such as TNF α-induced NF-κB inhibitory, antibacterial, and antibiofilm activities (Figure 1).2

Figure 1. Representative bioactive compounds containing a spirooxindole lactone skeleton.

Over the past decade, the significance of these spirooxindole lactone scaffolds has led to a demand for efficient synthetic methods, particularly those producing enantiomerically pure spirooxindole lactones.3 Among these, 3-hydroxyoxindoles, which have been demonstrated to be effective nucleophiles for the preparation of structurally diverse spirooxindoles,4 are expected to be effective substrates for use in Michael/ cyclization (Scheme 1). As a pioneer work, Melchiorre’s group reported the enamine catalyzed asymmetric synthesis of spirooxindole γ-butyrolactones with 3-hydroxyindole as a nucleophile.5 Subsequently, Trost and co-workers developed © XXXX American Chemical Society

a zinc-ProPhenol-catalyzed Michael/transesterification process to construct this related framework.6 Next, Wang’s and Received: December 18, 2018

A

DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

Kesavan’s groups independently described the asymmetric sequential allylic alkylation-cyclization of Morita-Baylis-Hillman carbonates and 3-hydroxyoxindoles.7,8 Recently, the use of α,β-unsaturated acyl phosphonates and N-acylated succinimides as the Michael acceptors for the synthesis of chiral spirooxindole γ-lactones was well exploited by Yuan and coworkers9 and Du and co-workers.10 Besides, NHC-catalyzed oxidative [3 + 2] annulation of dioxindoles with enals or saturated acid chlorides has been successfully realized by the groups of Biju,11 Ye,12 and Hui,13 respectively. In spite of these elegant advances, development of asymmetric strategies to construct structurally diverse spirooxindole γ-lactones for their pharmacological properties is still highly desirable. On the other hand, trifluoromethylated analogs of bioactive molecules have been found in many applications in chemical biology and drug discovery,14 which is ascribed to their unique physical, chemical, and physiological properties.15 Considering the structure−activity relationships used in drug design,16 the fusion of fluorinated-γ-lactones to oxindole would be a new type of potentially biologically active compounds. However, reports on the construction of these molecular fragments containing the CF3 group are extremely rare, despite their potential usefulness in many optically active pharmaceutical molecules.17 Therefore, the development of novel and more efficient methods for the preparation of fluorinated lactones remains an important, as well as challenging, goal in organic synthesis.18 In 2016, utilizing 3-trifluoroethylidene oxindoles as substrates have been successfully employed in the Friedel− Crafts alkylation/lactonization reaction developed by Zhao and co-workers, giving trifluoromethylated dihydrocoumarins in high stereoselectivities.19 Notably, the lactonization proceeded smoothly by nucleophilic attack of the naphthol hydroxy group at the chemically inert oxindole amide moiety under mild reaction conditions. Very recently, Bencivenni’s group reported the enantioselective vinylogous aldol-lactonization cascade reaction of alkylideneoxindole with trifluoromethyl ketones via oxindole amide C−N bond cleavage, affording a series of α,β-unsaturated δ-lactones bearing a CF3 group with high enantioselectivity.20 Encouraged by these achievements, we wondered whether 3hydroxyoxindoles could serve as binucleophiles in the Michael/lactonization cascade reaction with 3-trifluoroethylidene oxindoles. To the best of our knowledge, the asymmetric construction of trifluoromethylated spirooxindole lactones is entirely undeveloped. Herein, we are eager to report our research on this subject. To implement this hypothesis, we initiated our study by evaluating the reaction between 3-hydroxyoxindole 1a and 3trifluoroethylidene oxindole 2a with different bifunctional catalysts in CH2Cl2 at room temperature (Table 1 and Figure 2). When using Takemoto’s catalyst C1, the desired product 3aa was successfully produced in 13% yield with 94:6 dr and 91% ee (Table 1, entry 1). Encouraged by this promising result, a class of chiral squaramide/thiourea catalysts derived from cinchona alkaloid were then screened (Figure 1). To our delight, the quinidine-derived squaramide C7 was found to be the optimal choice in terms of yield and stereoselectivity (86% yield, 97:3 dr, and 97% ee) (Table 1, entry 7). The solvent effect on this reaction was then examined, and CH3CN proved to be efficient to access 3aa in 96% yield with slightly decreased enantioselectivity (93% ee) (entry 13). By comparison with the results of entries 7 and 13, the mixture of CH2Cl2 and CH3CN was further considered as the solvent by

entry

cat.

solvent

yield (%)b

dr (%)c

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19e 20f 21g

C1 C2 C3 C4 C5 C6 C7 C8 C9 C7 C7 C7 C7 C7 C7 C7 C7 C7 C7 C7 C7

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF toluene MeCN 1,4-dioxane DCE D/Md = 1/1 D/M = 5/1 D/M = 10/1 D/M = 10/1 D/M = 10/1 D/M = 10/1

13 25 75 17 21 74 86 75 16 72 84 41 96 61 72 95 94 96 72 56 75

94:6 83:17 97:3 88:12 91:9 98:2 97:3 97:3 63:37 97:3 93:7 87:13 97:3 92:7 95:5 97:3 97:3 98:2 96:4 97:3 97:3

91 −95 −97 −59 −94 −95 97 97 −76 97 87 94 93 93 93 93 97 97 94 94 95

a Reactions conditions: under nitrogen atmosphere, 1a (0.10 mmol), 2a (0.11 mmol), and catalyst (10 mol %) in 1.0 mL of solvent were stirred at room temperature for 12 h. bIsolated yield. cThe dr and ee were determined by chiral HPLC analysis; the ee refers to the major diastereomer. dD/M = CH2Cl2/MeCN (v/v). eReaction conducted at 0 °C. fReaction conducted at −20 °C. g5 mol % catalyst was used.

Figure 2. Bifunctional catalysts investigated in the reaction.

varying the ratio of volume (entries 16−18). Gratifyingly, the desired product 3aa could be furnished in 96% yield with excellent diastereo- and enantioselectivities (98:2 dr and 97% ee) in a 10/1 mixture of CH2Cl2 and CH3CN (entry 18). However, lowing the reaction temperature was detrimental for both reactivity and stereocontrol. Furthermore, lowering the catalyst loading to 5 mol % resulted in a decreased yield and stereoselectivity (entry 21). B

DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 3. Scope of the 3-Trifluoroethylidene Oxindolesa

Having ascertained the optimal conditions, we subsequently probed the generality of our protocol using 3-trifluoroethylidene oxindole 2a and a series of 3-hydroxyoxindole 1a−1l. As shown in Scheme 2, the corresponding spirooxindole γScheme 2. Scope of the 3-Hydroxyoxindolesa

a

See the notes in Scheme 2 and the Supporting Information for experimental detail.

product was observed when N-methyl substrate (2ad) was used as electrophile.21 The reactions proceeded well with electron-rich substituents on the oxindole ring (3ae and 3af). It was noted that substrates 2g−2l bearing an electronwithdrawing group (Cl, Br, F) gave the desired products 3ag− 3al in moderate yields (50−68%) with decreased diastereoselectivities (78:22−89:11 dr) and enanstereoselectivities (78%−90% ee). In addition, substrates with benzoylated or ester functionality substituted for the CF3 moiety (4a or 4b) were also investigated under optimized conditions (Scheme 4). Dis-

a

See the Supporting Information for experimental detail. bIsolated yields. cIn all cases, the dr and ee were determined by chiral HPLC analysis. dStructure and stereochemistry confirmed by X-ray analysis.

butyrolactones 3 were formed in high yields (70−97%) with excellent stereoselctivities (93:7−99:1 dr, 96−98% ee). Various halogens at the different positions of the aromatic rings were well tolerated, affording adducts 3ba−3ga in high yields with excellent diastereo- and enantiostereoselectivities (98:2−99:1 dr, 96−97% ee). An electron-donating group on the oxindole ring also worked well for the reaction (3ha and 3ia). When different N-protecting groups in 3-hydroxyindoles 1ja−1ka were subjected to the standard reaction conditions, products 3ja−3ka were isolated in 93−97% yields with excellent ee values (98% ee) and extraordinary diastereoselectivities (98:2 dr). Notably, the N-unprotected substrate 1la also proceeded smoothly to achieve the desired product 3la in 94% yield with 97:3 dr and 96% ee. The absolute configuration of the major diastereoisomer of 3da was determined as (2R,3R,4S) by X-ray analysis (details in the Supporting Information), and those of other products were assigned by analogy. Further exploration of the substrate scope was focused on diverse 3-trifluoroethylidene oxindoles 2b−2l, and the results were summarized in Scheme 3. Substituents on the 1-position of 2 were first studied. It was found that an electronwithdrawing group on the nitrogen atom of 2 was crucial for the cleavage of the amide moiety by the hydroxy group. Using substrates with carbonyl motif on the nitrogen atom (2b or 2c), the corresponding products 3ab and 3ac were formed in high yields with excellent stereoselectivities. However, no

Scheme 4. Study of 1 with Different EWGs of the Methyleneoxindolesa

a

See the Supporting Information for reaction conditions.

appointingly, desired products 5 were obtained with erosion of the yields and ee and dr values, which revealed that the CF3 moiety was essential for the high activity and stereocontrol. Finally, the utility of this methodology was evaluated. As shown in Scheme 5, the gram-scale synthesis of compound 3aa was facilely achieved with retained efficiency and stereochemical outcome (95% yield, 96:4 dr, 96% ee). Additionally, treatment of 3aa with HCl/MeOH formed 3-hydroxy oxindole C

DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Experimental details, characterization of new compounds, crystallographic data, and NMR and HPLC spectra (PDF)

Scheme 5. Gram-Scale Experiment and Chemical Transformation of Compound 3aa

Accession Codes

CCDC 1870595 contains 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], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

6 in high yield (93%) and 95% ee with inferior diastereoselectivity (1.2:1). On the basis of our experimental results and previous reports,9,10,19 a plausible reaction mechanism is outlined in Figure 3. With the dual-activation of chiral bifunctional

Wei-Ping Deng: 0000-0002-4232-1318 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work is supported by The Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (Nos. 21372074 and 21572053).

■ Figure 3. Proposed catalytic transition state.

squaramide-tertiary amine catalyst,22 the 3-hydroxyoxindole 1a was enolized by the tertiary amine moiety; concurrently, the two squaramide N−H bonds of catalyst coordinated with 3trifluoroethylidene oxindole 2a. Then, the enolized oxindole (Si-face) would attack the Cβ-position (Re-face) of 2a to favorably give intermediate A presumably due to the syn transfer of proton from the same side, which generates (2R,3R,4S)-3aa via the intramolecular lactonization, accompanied by the cleavage of the amide C−N bond. In summary, we have demonstrated an efficient method for the synthesis of densely functionalized spirooxindole γ-lactones bearing a CF3 moiety through an organocatalytic Michael/ lactonization domino reaction. Under mild conditions, the conversion of the chemically inert amide moiety of oxindoles into the lactone can be easily realized, delivering a series of CF3-containing spirooxindole γ-lactones in moderate to excellent yields (up to 97%), with good to excellent diastereoand enantioselectivities (up to 98:2 dr and 98% ee). Significantly, this protocol represents the first example of constructing optically pure fluorinated spirooxindole lactones, which shows great potential in medicinal chemistry. Further investigations aiming to elucidate the structure−activity relationship of these new compounds are underway.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04039. D

DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters synthesis of spirooxindoles: recent developments. Chem. Commun. 2018, 54, 6607. For selected examples, see: (f) Sun, L.-H.; Shen, L.T.; Ye, S. Highly diastereo- and enantioselective NHC-catalyzed [3 + 2] annulation of enals and isatins. Chem. Commun. 2011, 47, 10136. (g) Li, J.-L.; Sahoo, B.; Daniliuc, C.-G.; Glorius, F. Conjugate Umpolung of β,β-Disubstituted Enals by Dual Catalysis with an NHeterocyclic Carbene and a Brønsted Acid: Facile Construction of Contiguous Quaternary Stereocenters. Angew. Chem., Int. Ed. 2014, 53, 10515. (h) Zheng, C.; Yao, W.; Zhang, Y.; Ma, C. Chiral Spirooxindole-Butenolide Synthesis through Asymmetric N-Heterocyclic Carbene-Catalyzed Formal (3 + 2) Annulation of 3-Bromoenals and Isatins. Org. Lett. 2014, 16, 5028. (i) Xie, Y.; Yu, C.; Li, T.; Tu, S.; Yao, C. An NHC-Catalyzed In Situ Activation Strategy to βFunctionalize Saturated Carboxylic Acid: An Enantioselective Formal [3 + 2] Annulation for Spirocyclic Oxindolo-γ-butyrolactones. Chem. Eur. J. 2015, 21, 5355. (j) Xu, J.; Yuan, S.; Miao, M.; Chen, Z. 1Hydroxybenzotriazole-Assisted, N-Heterocyclic Carbene Catalyzed βFunctionalization of Saturated Carboxylic Esters: Access to Spirooxindole Lactones. J. Org. Chem. 2016, 81, 11454. (k) Reddi, Y.; Sunoj, R. B. Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone. ACS Catal. 2017, 7, 530. (l) Guo, Y.; Meng, C.; Liu, X.; Li, C.; Xia, A.; Xu, Z.; Xu, D. Successive Waste as Reagent: Two More Steps Forward in a Pinnick Oxidation. Org. Lett. 2018, 20, 913. (4) (a) Silvi, M.; Chatterjee, I.; Liu, Y.; Melchiorre, P. Controlling the Molecular Topology of Vinylogous Iminium Ions by Logical Substrate Design: Highly Regio- and Stereoselective Aminocatalytic 1,6-Addition to Linear 2,4-Dienals. Angew. Chem., Int. Ed. 2013, 52, 10780. (b) Cui, B. D.; Zuo, J.; Zhao, J. Q.; Zhou, M. Q.; Wu, Z. J.; Zhang, X. M.; Yuan, W. C. Tandem Michael Addition-Ring Transformation Reactions of 3-Hydroxyoxindoles/3-Aminooxindoles with Olefinic Azlactones: Direct Access to Structurally Diverse Spirocyclic Oxindoles. J. Org. Chem. 2014, 79, 5305. (5) Bergonzini, G.; Melchiorre, P. Controlling the Molecular Topology of Vinylogous Iminium Ions by Logical Substrate Design: Highly Regio- and Stereoselective Aminocatalytic 1,6-Addition to Linear 2,4-Dienals. Angew. Chem., Int. Ed. 2012, 51, 971. (6) Trost, B. M.; Hirano, K. Dinuclear Zinc Catalyzed Asymmetric Spirannulation Reaction: An Umpolung Strategy for Formation of αAlkylated-α-Hydroxyoxindoles. Org. Lett. 2012, 14, 2446. (7) Wang, Q.-L.; Peng, L.; Wang, F.-Y.; Zhang, M.-L.; Jia, L.-N.; Tian, F.; Xu, X.-Y.; Wang, L.-X. An Organocatalytic asymmetric sequential allylic alkylation-cyclization of Morita-Baylis-Hillman carbonates and 3-hydroxyoxindoles. Chem. Commun. 2013, 49, 9422. (8) Jayakumar, S.; Muthusamy, S.; Prakash, M.; Kesavan, V. Enantioselective Synthesis of Spirooxindole α-exo-Methylene-γbutyrolactones from 3-OBoc-Oxindoles. Eur. J. Org. Chem. 2014, 2014, 1893. (9) Chen, L.; Wu, Z.-J.; Zhang, M.-L.; Yue, D.-F.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Organocatalytic Asymmetric Michael/Cyclization Cascade Reactions of 3-Hydroxyoxindoles/3-Aminooxindoles with α,β-Unsaturated Acyl Phosphonates for the Construction of Spirocyclic Oxindole-γ-lactones/lactams. J. Org. Chem. 2015, 80, 12668. (10) Ming, S.; Zhao, B.-L.; Du, D.-M. Chiral squaramide-catalysed enantioselective Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturated N-acylated succinimides. Org. Biomol. Chem. 2017, 15, 6205. (11) Mukherjee, S.; Joseph, S.; Bhunia, A.; Gonnade, R. G.; Yetra, S. R.; Biju, A. T. Enantioselective synthesis of spiro γ-butyrolactones by N-heterocyclic carbene (NHC)-catalyzed formal [3 + 2] annulation of enals with 3-hydroxy oxindoles. Org. Biomol. Chem. 2017, 15, 2013. (12) (a) Chen, X.-Y.; Chen, K.-Q.; Sun, D.-D.; Ye, S. N-Heterocyclic carbine-catalyzed oxidative [3 + 2] annulation of dioxindoles and enals: cross coupling of homoenolate and enolate. Chem. Sci. 2017, 8, 1936. (b) Song, Z.-Y.; Chen, K.-Q.; Chen, X.-Y.; Ye, S. Diastereo- and Enantioselective Synthesis of Spirooxindoles with Contiguous

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DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (21) The desired product 3ad is not obtained, probably because no lactonization occurs. In addition, the Michael adduct is not formed due to the low reactivity of N-methyl substrate 2d, whereas the oxidation of dioxindole 1a to isatide primarily occurred under basic conditions, see ref 5. (22) For selected reviews on the bifunctional hydrogen bonding organocatalysis, see: (a) Ian Storer, R.; Aciro, C.; Jones, L. H. Squaramides: Physical Properties, Synthesis and Applications. Chem. Soc. Rev. 2011, 40, 2330. (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. - Eur. J. 2011, 17, 6890. (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253. (d) Zhao, B.-L.; Li, J.-H.; Du, D.-M. Squaramide-Catalyzed Asymmetric Reactions. Chem. Rec. 2017, 17, 994. For selected examples on substrates activation and selectivity, see: (e) Quintavalla, A.; Lanza, F.; Montroni, E.; Lombardo, M.; Trombini, C. Organocatalytic Conjugate Addition of Nitroalkanes to 3-Ylidene Oxindoles: A Stereocontrolled Diversity Oriented Route to Oxindole Derivatives. J. Org. Chem. 2013, 78, 12049. (f) Grayson, M. N. Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones. J. Org. Chem. 2017, 82, 4396. (g) Zhu, W.R.; Chen, Q.; Lin, N.; Chen, K.-B.; Zhang, Z.-W.; Fang, G.; Weng, J.; Lu, G. Organocatalytic Michael/cyclization cascade reactions of 3isothiocyanato oxindoles with 3-trifluoroethylidene oxindoles: an approach for the synthesis of 3′-trifluoromethyl substituted 3,2’pyrrolidinyl-bispirooxindoles. Org. Chem. Front. 2018, 5, 1375. (h) You, Y.; Lu, W.-Y.; Wang, Z.-H.; Chen, Y.-Z.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic Asymmetric [3 + 2] Cycloaddition of N-2,2,2-Trifluoroethylisatin Ketimines with β-Trifluoromethyl Electron Deficient Alkenes: Access to Vicinally Bis(trifluoromethyl)-Substituted 3,2’-Pyrrolidinyl Spirooxindoles. Org. Lett. 2018, 20, 4453.

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DOI: 10.1021/acs.orglett.8b04039 Org. Lett. XXXX, XXX, XXX−XXX