Letter pubs.acs.org/OrgLett
Development of Biligands Magnesium Catalysis in Asymmetric Conjugate Reactions of C3-Pyrrolyl-Oxindoles Kezhou Wang, Linqing Wang, Xihong Liu, Dan Li, Haiyong Zhu, Pengxin Wang, Yuyang Liu, Dongxu Yang,* and Rui Wang* School of Life Sciences, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China S Supporting Information *
ABSTRACT: A magnesium catalyzed asymmetric conjugate reaction of C3pyrrolyl-oxindoles with terminal alkynones is presented. The current asymmetric conjugate reaction relies on the development of novel combinational magnesium catalysis involving two chiral ligands. The current protocol proceeds smoothly and gives the corresponding enantioenriched 3,3-disubstituted oxindole skeletons with good enantioselectivities. Furthermore, the conjugate adducts could be transferred to spiro oxindole structures containing an eightmembered ring in high ee values.
T
at the C3-position will certainly result in different classes of 3,3disubstituted oxindole skeletons that may show promise as biologically active compounds.9 Here we report an asymmetric conjugate reaction between C3-pyrrolyl-oxindoles and alkynones mediated by Mg(II) catalysis. Our initial experiment began by evaluating a series of chiral ligands in the magnesium catalysis. As the results illustrate in Table 1, it was observed that simple BINOL derivatives did not give satisfactory enantioselectivities in the conjugate reaction as well as Z/E selective results. Then we turned our attention to the chiral oxazoline− OH ligands in magnesium catalysts recently developed by us. After a careful screening process, we identified L8 as a more potential chiral ligand in the Mg(II)-mediated asymmetric conjugate reaction, leading the desired conjugate adducts in 86:14 and 88.5:11.5 er value for the Z and E isomers, respectively (Table 1, entry 8). To further improve the enantioselectivities of the current Mg(II) catalyzed conjugate reaction between C3-pyrrolyloxindoles and alkynones, we next tried to investigate the effects of the second ligand in the magnesium catalysis. Initially, some nonchiral ligands were introduced into the catalytic method. However, these ligands did not give more promising results; only similar or decreased enantioselectivities occurred. It is notable that some ligands with stronger acidity, such as benzoic acid, would restrain the reaction. Inspired by recent works on the application of sulfinamides as chiral ligands in asymmetric synthesis,11 we attempted to introduce a series of simple sulfinamides into the magnesium catalysis. After the screening process, it was observed that some simple sulfinamides, such as commercially available tertbutanesulfinamide (B1 and B2), could obviously improve the enantioselectivities of the current Mg(II)-mediated conjugate
he development of effective catalytic methods plays a central role in asymmetric synthesis. In recent decades, tremendous work has been focused on designing and developing asymmetric catalysis involving chiral ligands in metal mediated reactions. In the research field of metal catalyzed asymmetric transformations, alkali and alkaline-earth metals, including magnesium (Mg),1 lithium (Li),2 and calcium (Ca),3 are often recognized as sustainable catalysts compared with noble metals. These cheap and widely existing metals have been applied to almost all types of classic asymmetric transformations. However, compared with the intense work on noble metals in asymmetric synthesis, the investigation of alkaline-earth metals is less developed. The design and development of novel catalytic strategies involving alkali or alkaline-earth metals is highly desirable. Recently, we have developed different magnesium catalytic methods and applied them to a series of asymmetric dearomatization, desymmetrization, and cyclization reactions.4−6 During the investigation of different magnesium catalysts and considering the valence state of magnesium itself, we wondered if more catalytic methods might be developed in magnesium catalysis by introducing two different ligands to the metal center. As the strategies documented in previous papers, the monoligand Mg(II) catalysts have been well studied,1 and there are also impressive reports on biligand magnesium catalytic methods in asymmetric reactions.7 On the basis of these well established studies, here we present a magnesium mediated asymmetric conjugate reaction of C3-pyrrolyloxindoles in the presence of two different chiral ligands. Although enormous synthetic efforts have been investigated in the development of various catalytic asymmetric methods for the construction of diverse 3,3-disubstituted oxindole skeletons in the past few years,8 work on catalytic asymmetric reactions concerning C3-pyrrolyl-oxindoles is very limited, and it is expected that assembly of different heterocycles with oxindoles © XXXX American Chemical Society
Received: July 6, 2017
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DOI: 10.1021/acs.orglett.7b02044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Substrate Scopea
Table 1. Optimization of the Mg(II)-Mediated Conjugate Reaction between C3-Pyrrolyl-oxindoles and Alkynonesa
erc entrya
L
E/Zb
Z
E
1 2 3 4 5 6 7 8
L1 L2 L3 L4 L5 L6 L7 L8
1:1 − 1:1 1:1.3 1.2:1 1.2:1 1:1 1.8:1
59.5:40.5 − 65.5:34.5 66.5:33.5 78.5:21.5 67.5:32.5 64.5:35.5 88.5:11.5
61.5:38.5 − 55.5:44.5 55.5:44.5 82.5:17.5 61.5:38.5 52.5:47.5 86:14
a
Reaction conditions: oxindole (1a, 0.10 mmol), alkynone (2a, 0.12 mmol) in toluene (1.0 mL) in presence of Bu2Mg (20 mol %) and L (20 mol %). bThe E/Z value of 3a was analyzed by NMR studies and chiral stationary phase HPLC. cThe er value of 3a was analyzed by chiral stationary phase HPLC. Note: Bu2Mg is 1.0 N in heptane.
Table 2. Optimization of the Tetrazoles Participating in Desymmetrization Reactiona
a
Reaction conditions: oxindole (1, 0.20 mmol), alkynone (2, 0.24 mmol) in toluene (1.0 mL) in presence of Bu2Mg (20 mol %), L8 (20 mol %), B2 (20 mol %), and 13x MS (50 mg).
reaction. The introduction of (R)-tert-butanesulfinamide (B2) gave slightly higher results. However, unluckily, the Z/E ratio was still not obviously improved. Next, detailed reaction conditions, such as solvents and temperatures, were screened. However, the solvent change to more polar THF or ether would prevent the conjugate reaction, which might be due to the coordination effects of these solvents to prevent the coordination process of substrates (Table 2, entries 6−8). To our delight, the introduction of molecular sieves obviously improved the results of the reaction between 1a and 2a, leading to higher ee values with enhanced Z/E ratios (Table 2, entries 9−12). With optimized conditions in hand for the Mg(II)-mediated asymmetric conjugate reaction between C3-pyrrolyl-oxindoles and alkynones, the substrate scope was investigated, and the olefin bond was reduced by H2 in the presence of Pd/C. As the results illustrate in Scheme 1, oxindoles with different electronic properties were reacted under the conditions, resulting in the corresponding adducts in moderate yields and good enantioselectivities (Scheme 1, 4a−4e). On the other hand, alkynones bearing substituents at different positions also collaborated in the asymmetric reaction, affording a series of C3 stereoselective
erc entrya
L
E/Zb
Z
E
1 2 3 4 5 6d 7e 8f 9g 10h 11i 12j
B1 B2 B3 B4 B5 B2 B2 B2 B2 B2 B2 B2
2:1 1:1 1:1 1:1 1:1 1:1 − − 3:1 3:1 3:1 3:1
86.5:13.5 88.5:11.5 86:14 85.5:14.5 86.5:13.5 52:45 − − 92:8 82.5:17.5 85.5:14.5 73.5:26.5
90.5:9.5 91.5:8.5 88:12 86.5:13.5 87.5:12.5 57.5:12.5 − − 93.5:6.5 86:14 92:8 88:12
a
Reaction conditions: oxindole (1a, 0.20 mmol), alkynone (2a, 0.24 mmol) in toluene (1.0 mL) in the presence of Bu2Mg (20 mol %) and L (20 mol %). bThe E/Z value of 3a was analyzed by NMR studies and chiral stationary phase HPLC. cThe ee value of 3a was analyzed by chiral stationary phase HPLC. dIn DCM. eIn THF. fIn ether. gWith 13x MS. hWith 3 Å MS. iWith 4 Å MS. jWith 5 Å MS. B
DOI: 10.1021/acs.orglett.7b02044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
Scheme 2. Transformation of the Conjugate Adducts and Relative X-ray Analysis
Rui Wang: 0000-0002-4719-9921 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSFC (21432003, 81473095, 21602091), the Program for Chang-jiang Scholars and Innovative Research Team in University (PCSIRT: No. IRT_15R27), and the Fundamental Research Funds for the Central Universities (lzujbky-2016-ct01, lzujbky-2017-k11, lzujbky-2015-k11, lzujbky-2017-19, lzujbky-2017-118).
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oxindoles with good enantioselectivities after the reduction process (Scheme 1, 4f−4o). Finally, some easily accessed transformations were carried out by utilization of the conjugate adduct 4d (Scheme 2). Treatment of 4d with vinylmagnesium bromide smoothly gave the corresponding tertiary alcohol 5. Interestingly, the tertiary alcohol 5 could be transferred to spiro oxindole 6 with the closing of an eight-membered ring under acidic conditions. The absolute configuration of 6 was determined by X-ray crystallographic analysis.10 However, the spiro oxindole structure 7 was not observed by treatment with some acidic conditions (Scheme 2). In summary, we have developed a magnesium catalyzed conjugate reaction between C3-pyrrolyl-oxindoles and alkynones. The catalytic asymmetric conjugate reaction is catalyzed by an in situ generated magnesium catalysis involving two chiral ligands. A series of enantioenriched 3,3-disubstituted oxindoles were generated after a simple reduction process. The conjugate adducts were transferred into spiro oxindole structures containing an eight-membered ring. Further investigation on combinational magnesium catalysis and mechanism study is still underway.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02044. Experimental procedures and spectroscopic data for all new compounds (PDF) Crystallographic data for 6 (CIF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Authors
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[email protected]. *E-mail:
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DOI: 10.1021/acs.orglett.7b02044 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters (9) (a) Cui, B.-D.; You, Y.; Zhao, J.-Q.; Zuo, J.; Wu, Z.-J.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Chem. Commun. 2015, 51, 757. (b) You, Y.; Cui, B.-D.; Zhou, M.-Q.; Zuo, J.; Zhao, J.-Q.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2015, 80, 5951. (c) You, Y.; Wu, Z.-J.; Wang, Z.-H.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2015, 80, 8470. (10) CCDC 1560066 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/data_request/cif. (11) For a recent review on sulfinamides as chiral ligands in asymmetric synthesis, see: Trost, B. M.; Rao, M. Angew. Chem., Int. Ed. 2015, 54, 5026.
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DOI: 10.1021/acs.orglett.7b02044 Org. Lett. XXXX, XXX, XXX−XXX
