Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereocontrolled Synthesis of Bispirooxindole-Based Hexahydroxanthones with Five Contiguous Stereocenters Xiong-Li Liu,*,†,‡ Gen Zhou,‡ Yi Gong,‡ Zhen Yao,‡ Xiong Zuo,‡ Wen-Hui Zhang,‡ and Ying Zhou*,†,‡ †
College of Pharmaceutical Sciences, Guizhou University of Chinese Medicine, Guiyang, Guizhou 550025, P.R. China Guizhou Engineering Center for Innovative Traditional Chinese Medicine and Ethnic Medicine, Guizhou University, Guiyang, Guizhou 550025, P.R. China
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‡
S Supporting Information *
ABSTRACT: A bifunctional oxindole−chromone synthon 1 directed tandem reaction is developed, serving as a fruitful strategy for facile access to optically active hexahydroxanthones 3 bearing two spirooxindoles with five contiguous stereocenters. All of the bispirooxindole-based hexahydroxanthones 3 are smoothly obtained with up to 91% yield, >20:1 dr, and >99% ee. Biological evaluation of selected compounds 3 revealed that they exerted good cytotoxic effects on human K562, A549, and PC-3 cells.
S
and in most cases, multiple steps are needed.4 Among the known methods,3a,4,5 use of readily available chromones as starting materials presents a promising one,5 which enables the construction of a cyclohexane structural unit in one step. However, the inherent inertness of the unactivated chromones, presumably due to the π-donor effect of the pyran oxygen atom, retards the development of this strategy. Jørgensen et al. disclosed an elegant catalytic asymmetric [4 + 2] cycloaddition to chiral tetrahydroxanthones with three contiguous stereocenters, using activated chromones as dienophiles.5a The electron-withdrawing cyano group played a crucial role in ensuring the high dienophilic reactivity (Scheme 1a). Recently, Mattson and co-workers6a developed the first chiral silanediol-catalyzed enantiocontrolled functionalization of chromones by in situ formation of benzopyrylium triflates6b,c followed by Mukaiyama reaction with silyl triflates in up to 56% ee (Scheme 1a). Although unactivated chromones have been used for catalytic enantioselective conjugate addition reactions using highly nucleophilic organometallic reagents, affording chiral flavanones with only one chiral center with excellent enantioselectivity,7 their use in the construction of hexahydroxanthones with multiple stereocenters was not investigated. Spirooxindoles8 were found in a number of natural and synthetic compounds with a wide range of biological activities. This is especially true for the past few years, which have seen a
mall molecules based on privileged natural product frameworks and rich in three-dimensional complexity are in high demand in drug-discovery programs.1 Therefore, new approaches to build novel and complex natural product-based scaffolds in an asymmetric manner remain highly desirable but challenging.2 In this context, hexahydroxanthone bearing four or more contiguous stereocenters represents a prominent structural motif encountered in a number of natural products and pharmacologically active compounds (Figure 1).3
Figure 1. Representative hexahydroxanthones bearing four or more stereocenters.
Efficient construction of complex molecules featuring a hexahydroxanthone core from simple chemicals in an operationally simple and stereochemically controllable fashion is highly desired. However, catalytic enantioselective synthesis of hexahydroxanthones with multiple stereocenters is still in its infancy, © XXXX American Chemical Society
Received: January 12, 2019
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DOI: 10.1021/acs.orglett.9b00139 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
found that the N-protection with Boc and Ac group in 1 and 2 respectivly is crucial for the high selectivity and yield (for detail, see Table S1 of SI). Several interesting features are notable in this reaction: organocatalytic enantioselective formal conjugate addition of the vinylogous ester function of unactivated chromone and enabled synthesis of bispirooxindole-based hexahydroxanthones with high efficiency and stereoselectivity. The substrate scope was then evaluated using the optimized conditions (Scheme 3). The reaction was generated with a wide variety of oxindole−chromones 1 and methyleneindolinones 2 to give diversely structured bispirooxindole-based hexahydroxanthones 3a−x in 62−91% yield with 94 to >99% ee and 10:1 to >20:1 dr. It is noteworthy that methyleneindolinones 2 with an electron-withdrawing substituent on the aromatic ring react much faster and gave higher yields than the ones with an electrondonating substituent. The presence of an electron-withdrawing group of methyleneindolinones 2 might decrease the electron density of the aromatic ring, thus accelerating the reaction. Moreover, the oxindole core could be modified, and the corresponding adducts were obtained with excellent selectivity (compounds 3w and 3x). The absolute configuration of chiral hexahydroxanthones 3e and 3g was unambiguously determined by X-ray crystallographic analysis and was found to be (C1′S,C2′R,C4′S,C5′S,C6′S). The absolute configuration of other corresponding cycloadducts 3 was assigned by analogy. To further highlight the synthetic value of the present approach, a large-scale experiment was conducted under the optimized conditions. The cascade reaction of 1 and 2 on a gram scale proceeded well, and product 3d was obtained in 80% yield with excellent selectivity being retained (for details, see the SI). The trans-relationship between the C1′ and C2′ stereogenic centers in the hexahydroxanthone unit of spiro-products 3 is similar to that present in the natural products, such as diversonol, desoxydiversonol, ergochrome DD, applanatin B, and isocochlioquinone A (Figure 1). This is different from the previous results by the groups of Jørgensen5a and Kumar,5d in which chiral tetrahydroxanthones with syn-chromanone moieties were obtained.12 The formed bispirooxindole-based hexahydroxanthones 3 were tested for their in vitro inhibitory activity against human K562 leukemia cells, human A549 lung cancer cells, and human PC-3 prostate cancer cells. Thus, nine selected compounds (3a, 3c, 3e, 3j, 3o, 3q, 3r, 3w, and 3x) were treated with the cell lines for 48 h, and the IC50 values were measured by the MTT-based assays13a,b using commercially available broad-spectrum anticancer drug cisplatin as a positive control. Most of the compounds showed considerable cytotoxicities to the cell lines of K562, A549, and PC-3 (Table 1), which showed activity comparable to that of cisplatin. Apoptosis is considered as a vital ingredient of various processes and features distinct morphological characteristics and biochemical mechanisms.13c,d AO/EB staining13e was performed to investigate morphological changes of K562 cells. The results are given in Figure S1A (for details, see SI). Treatments of K562 cells with compound 3a (1, 5, or 10 μM) for 36 h resulted in morphological changes with typical characteristics of apoptosis, such as nucleus shrinkage, condensation, and formation of apoptotic body-like vesicles, especially at high concentrations, indicating that compound 3a could induce apoptosis. To further explore the underlying mechanisms of compound 3a on cell apoptosis, K562 cells were incubated with various concentrations of compound 3a for 36 h and assayed for apoptosis with the Annexin-V-FITC/PI
Scheme 1. Chromone-Based DOS of Chiral Hydroxanthones Bearing Multiple Stereocenters
phenomenal increase in the number of reports on the synthesis of spirooxindoles, which may in part be ascribed to the increasing recognition of their biological significance.9 Encouraged by Jørgensen and Mattson’s pioneering work, we designed oxindole derived bifunctional chromone 1 which contains both a nucleophilic and an electrophilic center as a fourcarbon building block for the synthesis of chiral bispirooxindolebased hexahydroxanthones with five contiguous stereocenters (Scheme 1b). We synthesized the bifunctional oxindole−chromone 1, which can be readily accessed in three steps from chromone-3carbaldehyde and oxindole via a Knoevenagel condensation reaction and subsequent reduction (for details, see the Supporting Information (SI)). To test the hypothesis, we examined the reaction of 1 with methyleneindolinone 210 to construct the bispirooxindole-based hexahydroxanthone 3 with the quinine derived thiourea catalyst11 C1. Reaction of 1a and 2′a gave the desired bispirooxindole-based hexahydroxanthone 3′a in moderate yield and dr with excellent ee values. Use of the tert-butyl ester-substituted methyleneindolinone 2a furnished the desired product 3a with excellent diastereoselectivity (Scheme 2). Scheme 2. Bifunctional Oxindole−Chromone Synthon 1a Was Subjected to Domino Michael/Michael Reaction
Subsequently, we explored the effects of the N-protecting group of the oxindole core in 1 and 2 with C1 as catalyst. It was B
DOI: 10.1021/acs.orglett.9b00139 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Substrate Scope to Bispirooxindole-Based Hexahydroxanthones 3a
a Reactions were conducted with 1 (0.10 mmol), 2 (0.15 mmol), C1 (10 mol %), 60 mg of 5 Å MS in 2.5 mL of Et2O at rt for 3 days. Diastereomeric ratios were determined by 1H NMR, and enantiomeric ratios were determined by chiral HPLC.
double staining flow cytometry method. Treatment of K562 cells with 3a caused significant induction of apoptosis in a concentrationdependent manner (for detail, see Figure S1B). These results revealed that the inhibition of the proliferative of K562 cells could be attributed to the induction of apoptosis by compound 3a. In conclusion, we demonstrated that a donor/acceptor-based oxindole−chromone is useful for stereocontrolled synthesis of a new class of structurally rigid bispirooxindole-based hexahydroxanthones with five contiguous stereocenters. Preliminary screening of these compounds for the antitumor activity revealed that they are moderately active against the in vitro inhibition of K562 cell lines.
Table 1. Cell Inhibitory Assay of Functionalized Hexahydroxanthones in K562, A549, and PC-3 Cells IC50 (μM)a compound
K562
A549
PC-3
3a 3c 3e 3j 3o 3q 3r 3w 3x cisplatin
6.41 4.35 8.54 6.12 5.32 4.15 4.27 5.71 5.34 17.58
21.75 19.34 49.81 >100.00 53.78 45.24 27.63 >100.00 >100.00 13.84
45.09 25.05 50.21 48.90 40.57 31.13 32.44 24.90 28.37 21.29
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ASSOCIATED CONTENT
S Supporting Information *
a IC50 is the concentration of a compound that affords a 50% reduction in cell growth (after 48 h of incubation), expressed as the mean of triplicate experiments.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00139. C
DOI: 10.1021/acs.orglett.9b00139 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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Details of reaction conditions screening, all experimental procedures, and spectroscopic data of new compounds (PDF) Accession Codes
CCDC 1862472, 1862489, and 1875233 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], 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
Xiong-Li Liu: 0000-0001-5188-6970 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from NSFC (81760625, 81660576, and 81560563) and projects of Guizhou Province (Qian Ke He Zi [2015]4001, [2015]4032, [2016]5623, [2017]5609, and JG[2016]06) is appreciated.
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DOI: 10.1021/acs.orglett.9b00139 Org. Lett. XXXX, XXX, XXX−XXX
