(E)-3-(1-亚胺基乙基)-5, 5-二取代-4-甲氨基呋喃-2(5H)-酮的合成及其意外的杀虫活性

赵宇 刘鑫磊 李益豪 许磊川 苏彦豪 蒋家珍 王明安

引用本文: 赵宇, 刘鑫磊, 李益豪, 许磊川, 苏彦豪, 蒋家珍, 王明安. (E)-3-(1-亚胺基乙基)-5, 5-二取代-4-甲氨基呋喃-2(5H)-酮的合成及其意外的杀虫活性[J]. 有机化学, 2020, 40(8): 2547-2554. doi: 10.6023/cjoc202004050 shu
Citation:  Zhao Yu, Liu Xinlei, Li Yihao, Xu Leichuan, Su Yanhao, Jiang Jiazhen, Wang Ming'an. Synthesis and Unexpected Insecticidal Activity of (E)-3-(1-Imino-ethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one[J]. Chinese Journal of Organic Chemistry, 2020, 40(8): 2547-2554. doi: 10.6023/cjoc202004050 shu

(E)-3-(1-亚胺基乙基)-5, 5-二取代-4-甲氨基呋喃-2(5H)-酮的合成及其意外的杀虫活性

    通讯作者: 王明安, wangma@cau.edu.cn
  • 基金项目:

    国家自然科学基金(No.21772229)资助项目

摘要: 为了提高化合物对植物病原菌的杀菌活性及扩大多样性导向合成策略建立的分子库,以甲氨基替换3-(1-亚胺基乙基)-5,5-二取代-4-苯基呋喃-2(5H)-酮的苯基,设计合成了18个新颖的(E)-3-(1-亚胺基乙基)-5,5-二取代-4-甲氨基呋喃-2(5H)-酮,结构经过1H NMR,13C NMR,HR-ESI-MS表征.(E)-3-(1-(4-甲氧基苄氧亚胺基)乙基)-4-甲氨基-1-氧杂螺[4.5]癸-3-烯-2-酮(5O)还经过X射线衍射表征.生物活性测试结果表明,所有化合物对测试的四种植物病原菌均未显示明显的活体杀菌活性,但是意外地发现多个化合物在600 μg/mL浓度时对桃蚜、粘虫和小菜蛾的致死率均为100%,显示出良好的杀虫活性.

English

  • In the development courses of novel pesticides, several kinds of compounds were designed and synthesized based on the spirocyclic butenolide moiety using the strategy of diversity-oriented synthesis, [1-3] and most of compounds from our constructed molecular library (Scheme 1) were found to exhibit excellent fungicidal and insecticidal activities against several phytopathogens and harmful insects in our laboratory.[4-12] These results showed that our compounds derived from the spirocyclic butenolide moiety by diversity-oriented synthesis strategy exhibit the wide-range bioactivities in both fungicide and insecticide.

    Scheme 1

    Scheme 1.  Spirocyclic butenolide molecular library constructed from the diversity-oriented synthesis strategy[4-12]

    4-Aminofuran-2(5H)-ones are of interest as the biologically active compounds and intermediates in the synthesis of natural products.[13] For example, a novel insecticide 4-((N-2, 2-difluoroethyl)(N-6-chloropyridin-3-ylmethyl)-amino)-furan-2(5H)-one (flupyradifurone) with the 4- amino-furan-2(5H)-one and pyridin-3-ylmethyl moieties was available in the market since 2014, and it showed excellent activity against several harmful pests without the severe honeybee toxicity associating with the other neonicotinoid insecticides.[14] The 3-acetyl-4-phenyl-1-oxaspiro[4, 5]dec-3-en-2-one oxime derivatives (Scheme 2, A) were synthesized based on the facts that lots of compounds containing oxime ether scaffolds have excellent fungicidal activities, [15-18] and 3-acetyl-5, 5-dimethyl-4-(methylami- no)furan-2(5H)-one and 3-acetyl-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (Scheme 2, B) were also found to exhibit good in vivo fungicidal activities against E. graminis, P. polysora and C. lagenarium in the previous reports.[9-10] In order to improve the fungicidal activities against phytopathogens and enlarge the constructed molecular library, the C-4 phenyl group of 3-(1-iminoethyl)- 5, 5-disubstituted-4-phenylfuran-2(5H)-one was replaced with the methylamino group to design the novel molecule 3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one (Scheme 2). The synthetic route of target compounds was showed in Scheme 3. The synthesis and their biological activities of them were presented.

    Scheme 2

    Scheme 2.  Design strategy of target molecules

    Scheme 3

    Scheme 3.  Synthetic route of (E)-3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one

    1A, 2A, 2a, 3A~3I, 4A~4I, 5A~5I: R1=R2=CH3; 1B, 2B, 2b, 3J~3R, 4J~4R, 5J~5R: R1+R2=(CH2)5; 3A, 4A, 5A, 3J, 4J, 5J: R3=CH3; 3B, 4B, 5B, 3K, 4K, 5K: R3=PhCH2; 3C, 4C, 5C, 3L, 4L, 5L: R3=2-ClC6H4CH2; 3D, 4D, 5D, 3M, 4M, 5M: R3=3-ClC6H4CH2; 3E, 4E, 5E, 3N, 4N, 5N: R3=4-ClC6H4CH2; 3F, 4F, 5F, 3O, 4O, 5O: R3=4-CH3OC6H4CH2; 3G, 4G, 5G, 3P, 4P, 5P: R3=4-NO2C6H4CH2; 3H, 4H, 5H, 3Q, 4Q, 5Q: R3=3, 4-Cl2C6H3CH2; 3I, 4I, 5I, 3R, 4R, 5R: R3=2-Cl-6-FC6H3CH2
    Reagents and condition: (a) diketene, Et3N, Na, toluene, 70 ℃, 90%~93%; (b) Me3OBF4, (1, 8-bis(dimethylamino)naphthalene, DCM, reflux; 30% methylamine solution, ethanol, reflux, 55%~60%; (c) and (d) O-methyl/benzylhydroxylamine, 4-methylbenzenesulfonic acid, r.t. or reflux, 66%~72%; (e) oxalyl dichloride, DMF, 0 ℃~r.t.; (f) 30% methylamine solution, THF, r.t., 61%~78%

    When 2a and 2b were obtained, the direct oximination of 2a and 2b with O-benzylhydroxylamine or O-methyl- hydroxylamine in route 1 was performed under ambient or reflux temperature, but the raw materials were observed unchanged by thin-layer chromatography (TLC) check. The possible reason was that the proton of NH at C-4 formed strong six-membered hydrogen bond with the oxygen of carbonyl at C-3. In this case, the strategy was changed as indicated in route 2 in the Scheme 3. The direct oximination of intermediates 2A and 2B with O-benzyl- hydroxylamine or O-methyl hydroxylamine were going smoothly under reflux temperature and afforded oxime ether derivatives 3A~3R successfully. Then the oxime ether derivatives 3A~3R reacted with oxalyl dichloride using N, N'-dimethylformamide (DMF) as the catalyst to produce chlorinated products 4A~4R, which was utilized for the next reaction without purification. Finally, the target compounds 5A~5R were obtained by the reaction of 4A~4R with 30% (mass fraction) methylamine aqueous solution in 61%~78% overall yield for two steps from 3A~3R.

    The structures of the target compounds 5A~5R were characterized by the 1H NMR, 13C NMR, and HR-ESI-MS spectral data. In order to further confirm their structures and determine the configuration of C=N double bond of the oxime moiety in these molecules, the crystal of 5O was obtained from its ethanol/n-hexane solution, and the X-ray diffraction analysis result is depicated in Figure 1. This result indicated that the C=N double bond take E-configuration, and the proton of NH at C-4 formed strong six-membered hydrogen bond with the nitrogen atom of the oxime moiety at C-3. The intermolecular hexatomic hydrogen bond may contribute to stabilize the structure of B-conformation. The chemical shifts of the NH protons at C-4 were in the range of δ 8.40~8.80, the N-CH3 in the range of δ 2.95~3.17 were splitted into doublets with coupling constants 5.7 Hz in their 1H NMR spectra due to the presence of six-membered hydrogen bond. The δC of the C=N double bond of oxime moiety were in the range of 155.3~156.8, and the δC of N-CH3 were in the range of 11.1~11.6 in their 13C NMR spectra.

    图 1

    图 1.  X-Ray structure and two possible conformations of compound 5O

    After completed these syntheses, the 4-methylamino analogues of 3-(1-iminoethyl)-5, 5-disubstituted-4-phenyl-furan-2(5H)-one were evaluated for their fungicidal and insecticidal activities against several phytopathogens and harmful insects using protocol in the previous report.[9-12, 19-20] It was found that all of new compounds did not exhibit significant in vivo fungicidal activities (data do not give) against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia polysora and Colletotriechum agenarium as those 3-(1-iminoethyl)-5, 5-disubstituted-4- phenylfuran-2(5H)-one in the previous report.[9] This result indicated that the replacement of phenyl with methylamino at 4-position greatly decreased the in vivo fungicidal activities compared with that of 3-(1-iminoethyl)-5, 5-disub- stituted-4-phenylfuran-2(5H)-one. However some of them unexpectedly exhibited good insecticidal activities with 100% mortality against Plutella xylostella, Mythimna seprata and Myzus persicae, while they did not have acaricidal activities against Tetranychus cinnabarinus at the concentration of 600 µg/mL (Table 1). These results in Table 1 indicated that these compounds with 5, 5-germial dimethyl have better insecticidal activities than these compounds with 5, 5-spirocyclic, which implied that these bulky hindrance of 5, 5-spirocyclic group resulted in decreasing of insecticidal activity.[12] In the other aspect, those compounds with Cl-substitutition in the benzene ring were beneficial to improve insecticidal activity, while OCH3 and NO2 substitutition resulted in decreasing of their insecticidal activities. Compounds 5C, 5D, 5F, 5I, 5L and 5Q still had 30%~60% and 0~40% mortality against P. xylostella when the concentrations were decreased to 100 and 10 µg/mL, which indicated that these compounds could be used as the lead compounds for the further modification.

    表 1

    表 1  Insecticidal activities (mortality/%) of title compounds 5A~5R at 600 µg/mL
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    Compd. P. xylostella M. separata M. persicae T. cinnabarinus
    5A 0 0 100, 0, a 0b 0
    5B 0 0 0 0
    5C 100, 50, a 40b 0 0 0
    5D 100, 50, a 20b 0 0 0
    5E 0 0 0 50
    5F 100, 30, a 0b 0 0 0
    5G 60 50 0 0
    5H 0 0 0 0
    5I 100, 60, a 40b 0 0 0
    5J 70 0 0 0
    5K 70 100, 0, a 0b 0 0
    5L 100, 30, a 0b 0 0 0
    5M 0 0 0 0
    5N 0 70 0 0
    5O 0 0 0 0
    5P 50 50 0 0
    5Q 100, 50, a 0b 100, 0, a 0b 0 0
    5R 0 0 0 0
    Imidacloprid 100b 100b 100b 100b
    a Activity at 100 µg/mL; b Activity at 10 µg/mL.

    In summary, eighteen novel (E)-3-(1-iminoethyl)-5, 5- disubstituted-4-(methylamino)furan-2(5H)-one compounds were designed and synthesized in 61%~78% yields through four-step reaction using methyl 2-hydroxy-2- methylpropanoate and methyl 1-hydroxycyclohexane-1- carboxylate as the raw materials. Their structures were characterized by 1H NMR, 13C NMR, HR-ESI-MS data and confirmed by the X-ray diffraction of compound 5O. Compounds 5C, 5D, 5F, 5I, 5L and 5Q exhibited 100% mortality against P. xylostella, 5K and 5Q had 100% mortality against M. seprata, 5A had 100% mortality against M. persicae at the concentration of 600 μg/mL, respectively, while all of these compounds did not show significant in vivo fungicidal activities against phytopathogen P. cubensis, E. graminis, P. polysora and C. agenarium and acaricidal activities against T. cinnabarinus.

    Melting points (m.p.) were examined using a Yanagimoto apparatus without further corrected. 1H NMR and 13C NMR spectra were recorded on a Bruker DPX 300 spectrometer with CDCl3 as the solvents and tetramethylsilane (TMS) as the internal standard. HR-ESI-MS data were acquired on a Linear Trap Quadropole (LTQ) Orbitrap instrument equipped with electrospray ionization source (ESI). Crystal structure was analyzed at a Thermo Fisher ESCALAB 250 X-ray diffractometry. All chemicals such as starting materials and reagents were purchased from commercial supplier (Energy Chemical) and used without further purification except as indicated. Organic solvents were concentrated under reduced pressure using a rotary evaporator or oil pump. All reactions were carried out using magnetic stirring. The silica gel chromatography was performed using 200~300 mesh flash silca gel (Qingdao Haiyang).

    4.2.1   Synthesis of intermediates 2A and 2B, 2a and 2b

    Intermediates 2A and 2B, 2a and 2b were synthesized following the literature procedures, and their analytical data were consistent with the reported data[5, 10-11].

    4.2.2   Synthesis of intermediates 3A~3R

    Taking 3K as an example, intermediate 2B (630 mg, 3 mmol) was added into 50 mL of methanol in a 100 mL three-necked flask, then gradually O-benzylhydroxylamine (406 mg, 3.3 mmol) and 4-methylbenzenesulfonic acid hydrate (95 mg, 0.5 mmol) were added into the solution at the room temperature. The resulting mixture was stirred, heated and kept to reflux for 8 h. After cooled to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, the solution was washed with water (50 mL×3). The water phase was re-extracted with ethyl acetate (50 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na2SO4. The solvent was removed, and the residue was subjected to flash column chromatography on silica gel and eluted with petroleum ether/EtOAc (V:V=1:1) to afford (E)-3-(1-((ben- zyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3K) (466 mg, yield 74%) as a white solid. Intermediates 3A~3R were prepared in the same protocol.

    (E)-3-(1-((Methoxy)imino)ethyl)-5, 5-dimethyl-4-hydro-xylfuran-2(5H)-one (3A): White solid, 358 mg, yield 72%. m.p. 85~87 ℃; 1H NMR (300 MHz, CDCl3) δ: 4.56 (s, 1H, OH), 3.83 (s, 3H, OCH3), 2.44 (s, 3H, N=CCH3), 1.31 (s, 6H, 2×CH3); HR-ESI-MS cacld for C9H14NO4 [M+H]+ 200.0917, found 200.0912.

    (E)-3-(1-((Benzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3B): Yellow solid, 481 mg, yield 70%. m.p. 63~64 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.45~7.33 (m, 5H, ArH), 5.03 (s, 2H, ArCH2), 4.61 (s, 1H, OH), 2.55 (s, 3H, N=CCH3), 1.40 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H18NO4 [M+H]+ 276.1230, found 276.1236.

    (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-hydroxyfuran-2(5H)-one (3C): White solid, 533 mg, yield 69%. m.p. 92~93 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.49~7.28 (m, 4H, ArH), 5.16 (s, 2H, ArCH2), 4.62 (s, 1H, OH), 2.43 (s, 3H, N=CCH3), 1.45 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H17ClNO4 [M+H]+ 310.0841, found 310.0837.

    (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3D): White solid 548 mg, yield 71%. m.p. 106~107 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.35~7.20 (m, 4H, ArH), 4.99 (s, 2H, ArCH2), 4.60 (s, 1H, OH), 2.42 (s, 3H, N=CCH3), 1.45 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H17ClNO4 [M+H]+ 310.0841, found 310.0842.

    (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-hydroxylfuran-2(5H)-one (3E): White solid, 601 mg, yield 65%. m.p. 116~119 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.35~7.27 (m, 2H, ArH), 6.97~6.86 (m, 2H, ArH), 4.92 (s, 2H, ArCH2), 4.62 (s, 1H, OH), 2.42 (s, 3H, N=CCH3), 1.42 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H17ClNO4 [M+H]+ 310.0841, found 310.0847.

    (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-5, 5-di-methyl-4-hydroxylfuran-2(5H)-one (3F): White solid, 613 mg, yield 67%. m. p. 95~98 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.43~7.37 (m, 2H, ArH), 7.37~7.29 (m, 2H, ArH), 5.00 (s, 2H, ArCH2), 4.60 (s, 1H, OH), 3.83 (s, 3H, OCH3), 2.42 (s, 3H, N=CCH3), 1.45 (s, 6H, 2×CH3); HR-ESI-MS cacld for C16H20NO5 [M+H]+ 306.1336, found 306.1332.

    (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxylfuran-2(5H)-one (3G): Yellow solid, 624 mg, yield 65%, m.p. 79~80 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.27 (d, J=8.7 Hz, 2H, ArH), 7.56 (d, J=8.7 Hz, 2H, ArH), 5.16 (s, 2H, ArCH2), 4.65 (s, 1H, OH), 2.46 (s, 3H, N=CCH3), 1.45 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H17N2O6 [M+H]+ 321.1081, found 321.1086.

    (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3H): White solid, 611 mg, yield 71%, m.p. 112~114 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.51~7.47 (m, 2H, ArH), 7.26~7.22 (m, 1H, ArH), 4.97 (s, 2H, ArCH2), 4.64 (s, 1H, OH), 2.42 (s, 3H, N=CCH3), 1.46 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H16Cl2NO4 [M+H]+344.0451, found 344.0455.

    (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-hydroxyfuran-2(5H)-one (3I): White solid, 572 mg, yield 70%. m.p. 115~117 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.34~7.23 (m, 2H, ArH), 7.08~7.00 (m, 1H, ArH), 5.21 (s, 2H, ArCH2), 4.62 (s, 1H, OH), 2.38 (s, 3H, N=CCH3), 1.45 (s, 6H, 2×CH3); HR-ESI-MS cacld for C15H16FClNO4 [M+H]+ 328.0746, found 328.0750.

    (E)-3-(1-((Methoxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (3J): White solid, 430 mg, yield 72%. m.p. 82~85 ℃; 1H NMR (300 MHz, CDCl3) δ: 4.56 (s, 1H, OH), 3.83 (s, 3H, OCH3), 2.43 (s, 3H, N=CCH3), 1.87~1.12 (m, 10H, 5×CH2); HR-ESI-MS cacld for C12H18NO4 [M+H]+ 240.1230, found 240.1235.

    (E)-3-(1-((Benzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (3K): White solid, 543 mg, yield 69%, m.p. 120~122 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.43~7.31 (m, 5H, ArH), 5.02 (s, 2H, ArCH2), 4.60 (s, 1H, OH), 2.43 (s, 3H, N=CCH3), 1.74~1.08 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H22NO4 [M+H]+ 316.1543, found 316.1548.

    (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3L): Yellow solid, 595 mg, yield 68%. m.p. 131~134 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.47~7.25 (m, 4H, ArH), 5.15 (s, 2H, ArCH2), 4.62 (s, 1H, OH), 2.43 (s, 3H, N=CCH3), 1.72~1.01 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H21ClNO4 [M+ H]+ 350.1154, found 350.1147.

    (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3M): Yellow solid, 601 mg, yield 70%. m.p. 115~118 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.38~7.26 (m, 4H, ArH), 4.97 (s, 2H, ArCH2), 4.61 (s, 1H, OH), 2.40 (s, 3H, N=CCH3), 1.71~1.03 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H21ClNO4 [M+H]+350.1154, found 350.1151.

    (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3N): White solid, 578 mg, yield 66%. m.p. 132~135 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.44~7.30 (m, 4H, ArH), 5.03 (s, 2H, ArCH2), 4.64 (s, 1H, OH), 2.39 (s, 3H, N=CCH3), 1.72~1.00 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H21ClNO4 [M+H]+350.1154, found 350.1148.

    (E)-3-(1-((4-Methoxybenzyl)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3O): White solid, 604 mg, yield 70%. m.p. 93~95 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.37 (d, J=8.7 Hz, 2H, ArH), 6.95 (d, J=8.7 Hz, 2H, ArH), 5.01 (s, 2H, ArCH2), 4.61 (s, 1H, OH), 3.75 (s, 3H, OCH3), 2.37 (s, 3H, N=CCH3), 1.71~1.23 (m, 10H, 5×CH2); HR-ESI-MS cacld for C19H24NO5 [M+H]+346.1649, found 346.1642.

    (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3P): Yellow solid, 603 mg, yield 67%. m.p. 75~78 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.32~8.24 (m, 2H, ArH), 7.61~7.54 (m, 2H, ArH), 5.19 (s, 2H, ArCH2), 4.64 (s, 1H, OH), 2.41 (s, 3H, N=CCH3), 1.71~1.02 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H21N2O6 [M+H]+ 361.1394, found 361.1388.

    (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3Q): Yellow solid, 653 mg, yield 68%. m.p. 99~102 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.54~7.48 (m, 2H, ArH), 7.31~7.22 (m, 1H, ArH), 5.02 (s, 2H, ArCH2), 4.60 (s, 1H, OH), 2.39 (s, 3H, N=CCH3), 1.81~1.03 (m, 10H, 5×CH2); HR-ESI- MS cacld for C18H20Cl2NO4 [M+H]+ 384.0764, found 384.0769.

    (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one (3R): White solid, 607 mg, yield 66%. m.p. 89~91 ℃; 1H NMR (300 MHz, CDCl3) δ: 7.39~7.24 (m, 2H, ArH), 7.13~7.02 (m, 1H, ArH), 5.27 (s, 2H, ArCH2), 4.62 (s, 1H, OH), 2.35 (s, 3H, N=CCH3), 1.84~1.01 (m, 10H, 5×CH2); HR-ESI-MS cacld for C18H20FClNO4 [M+H]+ 368.1059, found 368.1065.

    4.2.3   Synthesis of target compounds 5A~5R

    Taking 5K as an example, intermediate 3K (315 mg, 1 mmol) was added into 20 mL of CH2Cl2 in a 50 mL three- necked flask. After the mixture was cooled down to 0 ℃ in water-ice bath, 170 μL (2 mmol) of oxalyl dichloride and 15 μL (0.2 mmol) of DMF were dropped in a stirred condition. Then the reaction mixture was back to room temperature, and stirred for 4 h. 20 mL of water was added into the solution, and the organic phase was separated. The water phase was re-extracted with CH2Cl2 (20 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na2SO4. The solvent was removed, and the crude product 4K was obtained and utilized for the next reaction without further purification.

    Product 4K was dissolved in tetrahydrofuran (THF) (20 mL), 30% (mass fraction) methylamine aqueous solution (265 μL, 2.5 mmol) was added gradually into the solution. The mixture was stirred and reacted for 6 h at ambient temperature. Then the solvent was removed, and the residue was dissolved in 50 mL of ethyl acetate. The organic mixture was washed with NaHCO3 solution, and the water phase was re-extracted with ethyl acetate (50 mL×2), and the organic phase was combined. Then the organic phase was dried over anhydrous Na2SO4. The solvent was removed, and the residue was subjected to flash column chromatography on silica gel and eluted with petroleum ether/EtOAc (V:V=4:1) to afford (E)-3-(1-((benzyl- oxy)imino)ethyl)-4-methyl-amino-1-oxaspiro[4.5]dec-3-en-2-one (5K) (213 mg, yield 65%) as a white solid. The target compounds 5A~5R were synthesized in the same procedure.

    (E)-3-(1-((Methoxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5A): White solid, 155 mg, yield 78%. m.p. 102~103 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.80 (brs, 1H, NH), 3.84 (s, 3H, OCH3), 3.15 (d, J=5.7 Hz, 3H, NCH3), 2.29 (s, 3H, N=CCH3), 1.63 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.1, 170.0, 155.4, 88.0, 78.1, 61.3, 30.5, 24.5, 11.2; HR-ESI-MS cacld for C10H17N2O3 [M+H]+ 213.1234, found 213.1236.

    (E)-3-(1-((Benzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5B): Yellow liquid, 232 mg, yield 70%. 1H NMR (300 MHz, CDCl3) δ: 8.51 (brs, 1H, NH), 7.42~7.30 (m, 5H, ArH), 5.05 (s, 2H, ArCH2), 2.95 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.59 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.0, 170.0, 155.5, 137.9, 128.1, 127.9, 127.5, 88.3, 78.1, 75.3, 30.2, 24.4, 11.5; HR-ESI-MS cacld for C16H21N2O3 [M+H]+ 289.1547, found 289.1546.

    (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5C): White solid, 197 mg, yield 61%. m.p. 102~103 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.59 (brs, 1H, NH), 7.46~7.24 (m, 4H, ArH), 5.18 (s, 2H, ArCH2), 3.04 (d, J=5.4 Hz, 3H, NCH3), 2.37 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.1, 170.0, 156.1, 135.6, 133.0, 129.8, 129.1, 128.7, 126.5, 88.1, 78.1, 72.0, 30.4, 24.5, 11.5; HR-ESI-MS cacld for C16H20ClN2O3 [M+H]+323.1157, found 323.1154.

    (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5D): White solid, 203 mg, yield 63%. m.p. 85~87 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.47 (brs, 1H, NH), 7.38~7.23 (m, 4H, ArH), 5.00 (s, 2H, ArCH2), 3.00 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.1, 169.9, 156.0, 140.1, 133.9, 129.5, 127.9, 127.6, 125.9, 88.2, 78.1, 74.4, 30.3, 24.4, 11.5; HR-ESI-MS cacld for C16H20ClN2O3 [M+H]+ 323.1157, found 323.1152.

    (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-5, 5-dimeth-yl-4-(methylamino)furan-2(5H)-one (5E): White solid, 209 mg, yield 65%. m.p. 128~130 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.46 (brs, 1H, NH), 7.37~7.26 (m, 4H, ArH), 5.01 (s, 2H, ArCH2), 2.98 (d, J=5.7 Hz, 3H, NCH3), 2.34 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.1, 169.9, 155.9, 136.5, 133.3, 129.1, 128.2, 88.2, 78.1, 74.4, 30.3, 24.4, 11.5; HR-ESI-MS cacld for C16H20ClN2O3 [M+H]+ 323.1157, found 323.1162.

    (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-5, 5-dime-thyl-4-(methylamino)furan-2(5H)-one (5F): White solid, 194 mg, yield 61%. m.p. 117~119 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.59 (brs, 1H, NH), 7.31~7.24 (m, 2H, ArH), 6.94~6.84 (m, 2H, ArH), 4.97 (s, 2H, ArCH2), 3.81 (s, 3H, OCH3), 3.00 (d, J=5.4 Hz, 3H, NCH3), 2.32 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.0, 169.9, 159.0, 155.3, 130.0, 129.5, 113.5, 88.4, 78.1, 75.0, 55.0, 30.3, 24.5, 11.5; HR-ESI-MS cacld for C17H23N2O4 [M+H]+ 319.1652, found 319.1656.

    (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5G): Yellow solid, 151 mg, yield 69%. m.p. 111~113 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.42 (brs, 1H, NH), 8.24~8.21 (m, 2H, ArH), 7.53~7.50 (m, 2H, ArH), 5.15 (s, 2H, ArCH2), 3.00 (d, J=5.7 Hz, 3H, NCH3), 2.38 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.3, 169.7, 156.8, 147.2, 145.5, 127.8, 123.3, 88.1, 78.2, 73.9, 30.4, 24.4, 11.6; HR-ESI-MS cacld for C16H20N3O5 [M+H]+ 334.1397, found 334.1393.

    (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-5, 5-di-methyl-4-(methylamino)furan-2(5H)-one (5H): White solid, 232 mg, yield 65%. m.p. 106~108 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.45 (brs, 1H, NH), 7.47~7.43 (m, 2H, ArH), 7.23~7.19 (m, 1H, ArH), 4.98 (s, 2H, ArCH2), 3.02 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.61 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.2, 169.8, 156.4, 138.3, 132.1, 131.5, 130.2, 129.6, 127.1, 88.2, 78.2, 73.8, 30.4, 24.4, 11.5; HR-ESI-MS cacld for C16H19Cl2- N2O3 [M+H]+ 357.0767, found 357.0765.

    (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-5, 5-dimethyl-4-(methylamino)furan-2(5H)-one (5I): White solid, 211 mg, yield 62%. m.p. 128~130 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.76 (brs, 1H, NH), 7.31~7.21 (m, 2H, ArH), 7.05~6.98 (m, 1H, ArH), 5.23 (s, 2H, ArCH2), 3.11 (d, J=5.7 Hz, 3H, NCH3), 2.30 (s, 3H, N=CCH3), 1.60 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ: 172.1, 169.9, 161.8 (d, 1JFC=248.1 Hz), 156.2, 136.1 (d, 3JFC=5.7 Hz), 130.1 (d, 3JFC=9.8 Hz), 125.3 (d, 4JFC=3.4 Hz), 123.5 (d, 2JFC=17.8 Hz), 113.7 (d, 2JFC=23.1 Hz), 87.9, 78.0, 65.3 (d, 3JFC=2.1 Hz), 30.3, 24.4, 11.1; HR-ESI-MS cacld for C16H19ClFN2O3 [M+H]+ 341.1063, found 341.1068.

    (E)-3-(1-((Methoxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5J): White solid, 187 mg, yield 74%. m.p. 118~120 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.85 (brs, 1H, NH), 3.82 (s, 3H), 3.17 (d, J=5.5 Hz, 3H, NCH3), 2.28 (s, 3H, N=CCH3), 1.99~1.23 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.3, 155.6, 88.7, 80.1, 61.3, 32.5, 30.6, 24.3, 21.4, 11.3. HR-ESI-MS cacld for C13H21N2O3 [M+H]+253.1547, found 253.1542.

    (E)-3-(1-((Benzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5K): White solid, 213 mg, yield 65%. m.p. 164~166 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.57 (brs, 1H, NH), 7.40~7.30 (m, 5H, ArH), 5.04 (s, 2H, ArCH2), 2.99 (d, J=5.5 Hz, 3H, NCH3), 2.36 (s, 3H, N=CCH3), 1.94~1.22 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.3, 155.7, 138.0, 128.1, 127.9, 127.5, 89.0, 80.1, 75.2, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C19H25N2O3 [M+H]+ 329.1860, found 329.1865.

    (E)-3-(1-((2-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5L): Yellow solid, 236 mg, yield 65%. m.p. 160~161 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.64 (brs, 1H, NH), 7.45-7.22 (m, 4H, ArH), 5.17 (s, 2H, ArCH2), 3.07 (d, J=5.7 Hz, 3H, NCH3), 2.38 (s, 3H, N=CCH3), 1.97~1.14 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.3, 156.3, 135.6, 133.0, 129.8, 129.0, 128.7, 126.5, 88.8, 80.1, 72.0, 32.5, 30.5, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C19H24ClN2O3 [M+H]+ 363.1470, found 363.1466.

    (E)-3-(1-((3-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5M): Yellow solid, 243 mg, yield 67%. m.p. 117~118 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.53 (brs, 1H, NH), 7.35~7.23 (m, 4H, ArH), 4.99 (s, 2H, ArCH2), 3.03 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.96~1.13 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.2, 156.2, 140.1, 133.9, 129.5, 127.9, 127.6, 125.9, 88.9, 80.2, 74.4, 32.5, 30.5, 24.3, 21.4, 11.6. HR-ESI-MS cacld for C19H24ClN2O3 [M+H]+ 363.1470, found 363.1473.

    (E)-3-(1-((4-Chlorobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5N): White solid, 225 mg, yield 62%. m.p. 139~140 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.52 (brs, 1H, NH), 7.36~7.26 (m, 4H, ArH), 5.00 (s, 2H, ArCH2), 3.01 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.96~1.15 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.2, 156.1, 136.5, 133.3, 129.1, 128.2, 88.9, 80.2, 74.4, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C19H24ClN2O3 [M+H]+ 363.1470, found 363.1476.

    (E)-3-(1-((4-Methoxybenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5O): White solid, 189 mg, yield 73%. m.p. 135~137 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.65 (brs, 1H, NH), 7.32~7.26 (m, 2H, ArH), 6.93~6.88 (m, 2H, ArH), 4.96 (s, 2H, ArCH2), 3.81 (s, 3H), 3.04 (d, J=5.7 Hz, 3H, NCH3), 2.33 (s, 3H, N=CCH3), 1.96~1.17 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.8, 170.3, 159.0, 155.6, 130.0, 129.5, 113.5, 89.0, 80.1, 74.9, 55.0, 32.5, 30.4, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C20H27N2O4 [M+H]+ 359.1965, found 359.1969.

    (E)-3-(1-((4-Nitrobenzyloxy)imino)ethyl)-4-(methyl-amino)-1-oxaspiro[4.5]dec-3-en-2-one (5P): Yellow solid, 228 mg, yield 61%. m.p. 128~129 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.46 (brs, 1H, NH), 8.24~8.20 (m, 2H, ArH), 7.53~7.50 (m, 2H, ArH), 5.15 (s, 2H, ArCH2), 3.02 (d, J=5.7 Hz, 3H, NCH3), 2.39 (s, 3H, N=CCH3), 1.96~1.14 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 172.1, 170.1, 156.9, 147.2, 145.5, 127.8, 123.3, 88.8, 80.2, 73.9, 32.5, 30.5, 24.3, 21.4, 11.7; HR-ESI-MS cacld for C20H27N2O4 [M+H]+ 359.1965, found 359.1969.

    (E)-3-(1-((3, 4-Dichlorobenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5Q): Yellow solid, 270 mg, yield 68%. m.p. 131~133 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.49 (brs, 1H, NH), 7.46~7.43 (m, 2H, ArH), 7.22~7.18 (m, 1H, ArH), 4.97 (s, 2H, ArCH2), 3.05 (d, J=5.7 Hz, 3H, NCH3), 2.35 (s, 3H, N=CCH3), 1.96~1.18 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 172.0, 170.1, 156.5, 138.3, 132.1, 131.5, 130.2, 129.6, 127.1, 88.8, 80.2, 73.8, 32.5, 30.5, 24.3, 21.4, 11.6; HR-ESI-MS cacld for C19H23Cl2N2O3 [M+H]+ 397.1080, found 397.1075.

    (E)-3-(1-((2-Chloro-6-flurobenzyloxy)imino)ethyl)-4-(methylamino)-1-oxaspiro[4.5]dec-3-en-2-one (5R): White solid, 256 mg, yield 68%. m.p. 133~134 ℃; 1H NMR (300 MHz, CDCl3) δ: 8.81 (brs, 1H, NH), 7.31~7.20 (m, 2H, ArH), 7.05~6.98 (m, 1H, ArH), 5.22 (s, 2H, ArCH2), 3.14 (d, J=5.7 Hz, 3H, NCH3), 2.31 (s, 3H, N=CCH3), 1.99~1.15 (m, 10H, 5×CH2); 13C NMR (75 MHz, CDCl3) δ: 171.9, 170.2, 161.8 (d, 1JFC=247.9 Hz), 156.5, 136.2 (d, 3JFC=5.5 Hz), 130.0 (d, 3JFC=9.7 Hz), 125.2 (d, 4JFC=3.3 Hz), 123.5 (d, 2JFC=17.8 Hz), 113.6 (d, 2JFC=22.8 Hz), 88.6, 80.0, 65.3 (d, 3JFC=2.1 Hz), 32.5, 30.4, 24.3, 21.4, 11.2; HR-ESI-MS cacld for C19H23ClFN2O3 [M+H]+ 381.1376, found 381.1379.

    The crystal of 5O was obtained from ethanol/n-hexane (V:V=1:20) solution. Its structure parameters were shown as following: crystal size: 0.40 mm×0.35 mm×0.30 mm, formula C20H26N2O4, M=358.43, triclinic, a=0.76597(5) nm, b=0.99514(7) nm, c=1.28118(8) nm, α=100.566(5)°, β=101.600(5)°, γ=100.749(6)°, V=0.91476(10) nm3, ρ=1.301 mg/mm3, space group P-1, Z=2, μ(Mo Kα)=0.091 mm-1, F(000)=384, S=1.033. Totally 7790 reflections were measured at T=112.00 K, 4241 unique reflections (Rint=0.0260) were used for all calculations and structure refinement. The final R1=0.0551, wR2=0.1071 (all data). The crystallographic data of 5O have been deposited with the Cambridge Crystallographic Data Centre with the accession number (CCDC 1999989). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif.

    The fungicidal and insecticidal activities were evaluated using the protocols in the previous reports[9-12, 19-20].

    Supporting information  The 1H NMR, 13C NMR of 5A~5R, and X-ray diffraction data of 5O. The Supporting information is available free of charge via the Internet at http://sioc-journal.cn.


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  • Scheme 1  Spirocyclic butenolide molecular library constructed from the diversity-oriented synthesis strategy[4-12]

    Scheme 2  Design strategy of target molecules

    Scheme 3  Synthetic route of (E)-3-(1-iminoethyl)-5, 5-disubstituted-4-(methylamino)furan-2(5H)-one

    1A, 2A, 2a, 3A~3I, 4A~4I, 5A~5I: R1=R2=CH3; 1B, 2B, 2b, 3J~3R, 4J~4R, 5J~5R: R1+R2=(CH2)5; 3A, 4A, 5A, 3J, 4J, 5J: R3=CH3; 3B, 4B, 5B, 3K, 4K, 5K: R3=PhCH2; 3C, 4C, 5C, 3L, 4L, 5L: R3=2-ClC6H4CH2; 3D, 4D, 5D, 3M, 4M, 5M: R3=3-ClC6H4CH2; 3E, 4E, 5E, 3N, 4N, 5N: R3=4-ClC6H4CH2; 3F, 4F, 5F, 3O, 4O, 5O: R3=4-CH3OC6H4CH2; 3G, 4G, 5G, 3P, 4P, 5P: R3=4-NO2C6H4CH2; 3H, 4H, 5H, 3Q, 4Q, 5Q: R3=3, 4-Cl2C6H3CH2; 3I, 4I, 5I, 3R, 4R, 5R: R3=2-Cl-6-FC6H3CH2
    Reagents and condition: (a) diketene, Et3N, Na, toluene, 70 ℃, 90%~93%; (b) Me3OBF4, (1, 8-bis(dimethylamino)naphthalene, DCM, reflux; 30% methylamine solution, ethanol, reflux, 55%~60%; (c) and (d) O-methyl/benzylhydroxylamine, 4-methylbenzenesulfonic acid, r.t. or reflux, 66%~72%; (e) oxalyl dichloride, DMF, 0 ℃~r.t.; (f) 30% methylamine solution, THF, r.t., 61%~78%

    图 1  X-Ray structure and two possible conformations of compound 5O

    表 1  Insecticidal activities (mortality/%) of title compounds 5A~5R at 600 µg/mL

    Compd. P. xylostella M. separata M. persicae T. cinnabarinus
    5A 0 0 100, 0, a 0b 0
    5B 0 0 0 0
    5C 100, 50, a 40b 0 0 0
    5D 100, 50, a 20b 0 0 0
    5E 0 0 0 50
    5F 100, 30, a 0b 0 0 0
    5G 60 50 0 0
    5H 0 0 0 0
    5I 100, 60, a 40b 0 0 0
    5J 70 0 0 0
    5K 70 100, 0, a 0b 0 0
    5L 100, 30, a 0b 0 0 0
    5M 0 0 0 0
    5N 0 70 0 0
    5O 0 0 0 0
    5P 50 50 0 0
    5Q 100, 50, a 0b 100, 0, a 0b 0 0
    5R 0 0 0 0
    Imidacloprid 100b 100b 100b 100b
    a Activity at 100 µg/mL; b Activity at 10 µg/mL.
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  • 发布日期:  2020-08-25
  • 收稿日期:  2020-04-29
  • 修回日期:  2020-05-10
  • 网络出版日期:  2020-05-27
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