C-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究

吉玉 姚辉 柳乂 黄年玉 刘明国

引用本文: 吉玉, 姚辉, 柳乂, 黄年玉, 刘明国. C-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究[J]. 有机化学, 2020, 40(7): 2051-2061. doi: 10.6023/cjoc202003037 shu
Citation:  Ji Yu, Yao Hui, Liu Yi, Huang Nianyu, Liu Mingguo. Synthesis and Cytotoxic Activity of C-Vinyl-rhamnopyranoside Derivatives[J]. Chinese Journal of Organic Chemistry, 2020, 40(7): 2051-2061. doi: 10.6023/cjoc202003037 shu

C-乙烯基鼠李糖苷衍生物的合成及细胞毒活性探究

    通讯作者: 黄年玉, hny115@126.com; 刘明国, mgliu1966@163.com
  • 基金项目:

    国家自然科学基金(No.21602123)及三峡大学青年拔尖人才项目和研究生创新基金(No.SDYC2016121)资助项目

摘要: 报道了L-鼠李烯糖与炔丙酯在Au(Ⅰ)催化下通过分子间串联的1,3-酰氧基迁移/Ferrier重排策略,合成了C-乙烯基鼠李糖苷衍生物.通过同位素O18标记实验验证了C-糖基化机理.产物的绝对构型经X射线单晶衍射分析确定.利用噻唑蓝(MTT)法研究了产物的细胞毒活性,结果显示产物3i对人体胃癌细胞HGC-27具有良好的抑制作用,IC50值为18.29 μmol·L-1.该方法具有操作简单、高非对映选择性、反应条件温和等优点.

English

  • 碳苷作为一类重要的糖苷类化合物, 因其对酸水解和酶促水解均表现出高稳定性, 被认为是一种稳定的药效基团, 广泛应用于医药、化工等领域[1].其中, 鼠李糖碳苷衍生物是一类具有显著抗菌活性和抗肿瘤活性的化合物[2].近年来具有生物活性的鼠李糖碳苷类天然产物和药物分子相继被报道.例如Vineomycinone B2 methyl ester[3]、Polycarcinv[4]、7-O-Glycosyl genisteins[5].因此, 探索鼠李糖碳苷类化合物的高效合成在糖化学和医药研发领域具有重要的意义.

    过渡金属催化偶联反应是构建碳苷键最有效的方法之一[6].除了通过传统的催化偶联反应, 如Heck、Suzuki、Stille以及Negishi反应等, 近些年涌现出许多新型的金属催化体系, 提高了糖苷化反应的立体选择性[7].但是如何简单高效地实现异头碳原子上的区域选择性和α/β立体选择性, 依然是当今糖化学研究难点之一.其中, 通过过渡金属催化偶联反应合成含C-乙烯基骨架的糖苷类化合物, 作为一类重要的合成中间体[8], 以其显著抗菌活性、抗肿瘤活性[9], 引起合成化学家的广泛关注.目前, 合成C-乙烯基鼠李糖苷的例子很少.例如, 过渡金属催化的烯醇三氟甲磺酸酯与鼠李烯糖的交叉偶联反应合成C-乙烯基鼠李糖苷[10], 以及用Lewis酸催化的芳基乙炔与鼠李烯糖分子间串联的糖苷化反应和卤代过程合成C-乙烯基鼠李糖苷[11].为了进一步拓展此类化合物的合成方法, 本工作探究了Ph3PAuCl/ AgSbF6催化下L-鼠李烯糖与炔丙酯发生分子间串联的1, 3-酰氧基迁移/Ferrier重排, 探讨了高收率、高立体选择性地合成C-乙烯基鼠李糖苷的反应.

    为了获得C-乙烯基鼠李糖苷衍生物合成的最优反应条件, 本工作以L-鼠李烯糖(1a)和炔丙酯(2a)为模型反应, 首先评估了Au2O3、TiCl4、Ni(CO)4、PdCl2、Ag2CO3诱导1a发生Ferrier重排生成C-乙烯基糖苷产物的能力, 然而反应24 h未检测到目标产物(表 1, Entries 1~5).当使用AuCl3时, 室温条件反应6 h就能以21%的收率得到C-乙烯基鼠李糖苷产物3a(表 1, Entry 6).这一结果促使了对金催化剂进一步筛选(表 1, Entries 7~18), 最终确定Ph3PAuCl和AgSbF6组合催化剂的催化效果最佳, 能以58%的收率得到目标产物.随后对反应溶剂进行筛选(表 1, Entries 19~24), 发现以CH3NO2为溶剂时反应收率高, 达78%(表 1, Entry 22).最终确定了反应的最优条件:以CH3NO2为溶剂, Ph3PAuCl/AgSbF6 (5 mol%)为催化剂, 室温下反应6 h.

    表 1

    表 1  模型反应条件优化a
    Table 1.  Optimization of reaction conditions for the model reaction
    下载: 导出CSV
    Entry Catalyst Solvent Time/h Yieldb/%
    1 Au2O3 CH2Cl2 24 N.D.
    2 TiCl4 CH2Cl2 24 N.D.
    3 Ni(CO)4 CH2Cl2 24 N.D.
    4 PdCl2 CH2Cl2 24 N.D.
    5 Ag2CO3 CH2Cl2 24 N.D.
    6 AuCl3 CH2Cl2 6 21
    7 AuBr3 CH2Cl2 6 12
    8 AuCl CH2Cl2 6 31
    9 Ph3PAuCl CH2Cl2 24 N.D.
    10 AgSbF6 CH2Cl2 24 N.D.
    11 Au(CO)Cl/AgSbF6 CH2Cl2 6 24
    12 Ph3PAuCl/AgSbF6 CH2Cl2 6 58
    13 Ph3PAuNTf2/AgSbF6 CH2Cl2 6 42
    14 Ph3PAuCl/AgNO3 CH2Cl2 6 28
    15 Ph3PAuCl/CH3CO2Ag CH2Cl2 6 37
    16 Ph3PAuCl/Ag2CO3 CH2Cl2 6 45
    17 Ph3PAuCl/Ag3PO4 CH2Cl2 6 48
    18 (C5H5N)AuCl3/AgSbF6 CH2Cl2 6 46
    19 Ph3PAuCl/AgSbF6 DMF 6 N.D.
    20 Ph3PAuCl/AgSbF6 CHCl3 6 36
    21 Ph3PAuCl/AgSbF6 Toluene 6 25
    22 Ph3PAuCl/AgSbF6 CH3NO2 6 78
    23 Ph3PAuCl/AgSbF6 CH3CN 6 12
    24 Ph3PAuCl/AgSbF6 EtOAc 6 N.D.
    aGeneral conditions: catalyst (5 mol%) was added into the mixture of 1a (107 mg, 0.5 mmol) and 2a (113 mg, 0.5 mmol) in corresponding solvent (5 mL). b Isolated yield. N.D.=not detected.

    在最优条件下对炔丙酯的适用范围进行了筛选(表 2).当R1为苯基, R2为烷基时, 能够以良好的收率得到C-乙烯基鼠李糖苷衍生物, 且随着烷基(R2)空间位阻的增大, 收率有所降低(3a~3f).随后考察了苯环上所连取代基(R1)的电子效应对反应的影响, 发现供电子效应的取代基不利于提高衍生物的收率(3g~3i, 3j~3m), 而拉电子效应的取代基有利于衍生物收率的提高(3q~3t).当R1为杂环噻吩时, 能以68%的收率得到3u.当R1、R2均为烷基时, 也能以较高的收率获得目标产物(3v~3x).当R1为烷基, R2为芳基时, 同样也能获得较好的收率(3y).所得产物均为α构型, 通过对化合物3g的X射线单晶衍射分析也进一步验证了这一结果(图 1).

    表 2

    表 2  C-乙烯基鼠李糖苷衍生物的底物拓展
    Table 2.  Substrate scope for C--vinyl-rhamnopyranoside derivatives
    下载: 导出CSV

    图 1

    图 1.  化合物3g的晶体结构
    Figure 1.  X-ray single crystal structure of 3g

    为了研究鼠李烯糖保护基空间位阻的改变对反应的影响, 设计了实验(表 3).以苯甲酰基保护的鼠李烯糖(1b~1f)在上述最优条件下反应, 能以73%~78%的收率、高立体选择性得到C-乙烯基鼠李糖苷衍生4.烯糖保护基空间位阻的增大对反应收率和选择性几乎没有影响.通过上述实验说明, 该反应具有广泛的官能团耐受性和高非对映选择性, 为简单高效制备C-乙烯基鼠李糖苷衍生物提拱了新方法.

    表 3

    表 3  C-乙烯基鼠李糖苷衍生物的底物扩展
    Table 3.  Substrate expansion of C-vinyl-rhamnopyranoside derivatives
    下载: 导出CSV
    Entry R1 (1) R2 Yield/% (4)
    1 Ph (1b) Et 76 (4ba)
    2 Ph (1b) iBu 73 (4bb)
    3 2-ClC6H4 (1c) iBu 74 (4ca)
    4 3-ClC6H4 (1d) iBu 75 (4da)
    5 2-FC6H4 (1e) iBu 76 (4ea)
    6 4-FC6H4 (1f) iBu 78 (4fa)

    随后将该方法扩展到岩藻烯糖(1g)时, 发现对岩藻烯糖同样适用, 以高非对映选择性得到预期的C-乙烯基岩藻糖苷衍生物5 (Eq. 1), 其收率高于由鼠李烯糖反应时的产物.这可能是由于岩藻烯糖C4上基团的空间取向, 在糖苷化过程中更有利于联烯中间体的亲核进攻.

    (1)

    通过查阅相关文献[12], 提出了如下可能反应机理(Scheme 1).在反应过程中, 金催化剂不仅可以作为路易斯酸, 促使烯糖发生Ferrier重排生成氧鎓离子C, 也能活化炔键发生分子内环化生成A, 随后发生1, 3-酰氧基迁移生成联烯B, 进而对C发生亲核进攻, 氧鎓离子解离得到C-乙烯基鼠李糖苷E.

    图式 1

    图式 1.  可能的反应机理
    Scheme 1.  Possible reaction mechanism

    为了验证反应机理经历炔丙酯迁移过程, 设计了同位素标记实验.利用L-鼠李烯糖1a18O标记的炔丙酯2a-18O[13]在最优条件下进行反应, 从3a-18O13C NMR谱中可以清楚地看到18O标记的羰基碳在δ 198.76处有信号峰.同时, HRMS也证实了3a-18O的存在.这一结果充分证明炔丙酯在反应过程中发生了1, 3-酰氧基迁移(Eq. 2).

    (2)

    通常含有鼠李糖碳苷骨架的化合物具有良好的抗肿瘤活性, 促使我们对合成的新化合物3~5进行细胞毒活性研究.利用噻唑蓝(MTT)法, 选择三种人体癌细胞株[胃癌细胞(HGC-27)、宫颈癌细胞(Caski)和肝癌细胞(Hep-G2)]和人胃粘膜细胞(GES-1)进行体外细胞毒活性测试[14].通过SPSS 13.0软件分别计算化合物对于不同细胞的IC50值.测试结果(表 4)表明, 所有化合物对人胃粘膜细胞均表现出低毒性.化合物3i具有显著的体外胃癌细胞抑制增长活性, 其IC50值为18.29 μmol•L1.随着3i浓度的增加, 细胞毒活性也随之增加(图 2).

    表 4

    表 4  目标化合物的细胞毒活性
    Table 4.  Cytotoxic activity of target compounds
    下载: 导出CSV
    化合物 IC50值/(μmol•L1)
    胃癌细胞 宫颈癌细胞 肝癌细胞 人胃粘膜细胞
    3a~3h >100 >100 >100 >100
    3i 18.29 >100 >100 >100
    3j~3o >100 >100 >100 >100
    3p 82.91 >100 >100 >100
    3q~3y >100 >100 >100 >100
    4ba >100 >100 >100 >100
    4bb 90.21 >100 >100 >100
    4ca~4fa >100 >100 >100 >100
    5a~5b >100 >100 >100 >100

    图 2

    图 2.  化合物3i的胃癌细胞毒活性
    Figure 2.  Cytotoxities against HGC-27 cells of compound 3i

    在Au(Ⅰ)催化作用下, 炔丙酯与鼠李烯糖发生分子间串联的1, 3-酰氧基迁移/Ferrier重排反应, 以52%~92%的收率、高非对映选择性地合成了一系列C-乙烯基鼠李糖苷衍生物.通过1H NMR, 13C NMR以及X射线单晶衍射分析确定所得产物的绝对构型.将该方法扩展到其它烯糖底物来探索其更多的潜在药用价值将在未来的研究中相继开展.

    所有反应均在氮气氛围中进行.反应溶剂均参照标准方法进行无水无氧处理. Bruker AVANCE Ⅲ 400 MHz核磁共振仪, Oxford diffraction Gemini E型单晶衍射仪, Agilent 1290-6540 UHPLC Q-Tof型质谱仪.化合物1a~1f[15]2a~2y[16]参考文献方法制备.其他商品化试剂购买后, 无需纯化直接使用.

    3.2.1   化合物3a~3y的合成

    在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1a (107 mg, 0.5 mmol), 炔丙酯2 (0.5 mmol), CH3NO2 (5 mL), 室温搅拌10 min后, 迅速加入Ph3PAuCl (12.3 mg, 5 mol%)和AgSbF6 (6.5 mg, 5 mol%).室温下搅拌6 h, 薄层色谱(TLC)检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.通过硅胶快速色谱法(石油醚/乙酸乙酯, V:V=20:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物3.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3a):无色油状, 128 mg, 产率78%. 1H NMR (CDCl3, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.61~7.56 (m, 1H), 7.50~7.46 (m, 2H), 5.98 (ddd, J=10.3, 3.0, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J=7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.93~1.86 (m, 2H), 1.42~1.33 (m, 2H), 1.10 (d, J=6.4 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.9, 170.6, 138.5, 137.5, 135.3, 133.4, 130.0, 129.3, 128.7, 126.6, 73.1, 70.4, 66.9, 31.7, 22.4, 21.2, 17.5, 13.7. HRMS calcd for C20H24O4Na [M+Na]+ 351.1567, found 351.1565.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-庚基-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3b):无色油状, 133 mg, 产率78%. 1H NMR (CDCl3, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.60~7.56 (m, 1H), 7.49~7.45 (m, 2H), 5.98 (ddd, J=10.3, 3.0, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J=7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.97~1.86 (m, 2H), 1.34~1.29 (m, 2H), 1.22~1.16 (m, 2H), 1.11 (d, J=6.3 Hz, 3H), 0.78 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.9, 170.6, 138.4, 137.5, 135.5, 133.4, 130.1, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 31.3, 29.5, 22.2, 21.2, 17.5, 13.8. HRMS calcd for C21H26O4Na [M+Na]+ 365.1723, found 365.1724.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3c):无色油状, 130 mg, 产率76%. 1H NMR (CDCl3, 400 MHz) δ: 7.75~7.73 (m, 2H), 7.56~7.52 (m, 1H), 7.46~7.42 (m, 2H), 6.42 (t, J=7.6 Hz, 1H), 6.06 (dd, J=10.2, 1.9 Hz, 1H), 5.89 (ddd, J=10.3, 4.8, 2.6 Hz, 1H), 5.40~5.38 (m, 1H), 4.88~4.86 (m, 1H), 4.16 (qd, J=6.8, 2.4 Hz, 1H), 2.47 (t, J=7.2 Hz, 2H), 2.09 (s, 3H), 1.74~1.67 (m, 1H), 1.32 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.6, 170.8, 149.5, 138.7, 138.1, 133.7, 132.0, 129.6, 128.1, 120.6, 71.0, 68.4, 66.0, 37.3, 28.7, 22.7, 22.6, 21.2, 16.0. HRMS calcd for C21H26O4Na [M+Na]+ 365.1723, found 365.1724.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3d):无色油状, 118 mg, 产率72%. 1H NMR (CDCl3, 400 MHz) δ: 7.94~7.91 (m, 2H), 7.60~7.56 (m, 1H), 7.50~7.46 (m, 2H), 5.97 (ddd, J=10.3, 2.9, 1.6 Hz, 1H), 5.90~5.87 (m, 1H), 5.67 (dd, J=10.6, 1.2 Hz, 1H), 5.05~5.03 (m, 1H), 4.99 (dq, J=7.6, 2.2 Hz, 1H), 3.83~3.77 (m, 1H), 2.28~2.19 (m, 1H), 2.08 (s, 3H), 1.11 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.7, 170.5, 141.5, 137.5, 136.2, 133.4, 130.0, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 29.0, 22.7, 22.4, 21.2, 17.5. HRMS calcd for C20H24O4Na [M+Na]+ 351.1567, found 351.1566.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4, 4-二甲基-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3e):无色油状, 111 mg, 产率65%. 1H NMR (CDCl3, 400 MHz) δ: 7.98~7.96 (m, 2H), 7.59~7.56 (m, 1H), 7.49~7.46 (m, 2H), 5.96 (ddd, J=10.3, 2.9, 1.6 Hz, 1H), 5.86 (dt, J=10.4, 2.1 Hz, 1H), 5.73 (d, J=1.1 Hz, 1H), 4.94 (dq, J=7.3, 2.2 Hz, 1H), 4.85 (br, 1H), 3.78~3.71 (m, 1H), 2.05 (s, 3H), 1.08 (d, J=6.4 Hz, 3H), 1.01 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 199.4, 170.6, 143.3, 137.5, 135.1, 133.3, 130.2, 129.6, 128.5, 126.3, 74.4, 70.3, 67.0, 34.1, 30.2, 21.1, 17.4. HRMS calcd for C21H26O4Na [M+Na]+ 365.1723, found 365.1736.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1, 5-二苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3f):黄色油状, 144 mg, 产率74%. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (d, J=7.5 Hz, 2H), 7.58~7.54 (m, 1H), 7.44~7.41 (m, 2H), 7.26~7.15 (m, 3H), 7.01 (d, J=7.2 Hz, 2H), 5.96~5.87 (m, 3H), 5.04 (br, 1H), 5.00 (dd, J=7.6, 1.2 Hz, 1H), 3.82~3.75 (m, 1H), 2.66 (t, J=7.6 Hz, 2H), 2.27~2.21 (m, 2H), 2.10 (s, 3H), 1.09 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.7, 170.5, 140.8, 139.1, 137.3, 134.2, 133.5, 129.9, 129.2, 128.7, 128.5, 128.4, 126.8, 126.2, 126.1, 73.1, 70.4, 66.8, 35.4, 35.2, 31.6, 21.2, 17.6. HRMS calcd for C21H27O4 [M+H]+ 391.1904, found 391.1910.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(对甲苯基)-5-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3g):无色油状, 131 mg, 产率65%. 1H NMR (CDCl3, 400 MHz) δ: 7.72~7.70 (m, 2H), 7.24~7.15 (m, 5H), 7.03~7.00 (m, 2H), 5.94 (ddd, J=10.3, 2.8, 1.5 Hz, 1H), 5.91~5.85 (m, 2H), 5.03 (br, 1H), 4.99 (dq, J=7.6, 2.0 Hz, 1H), 3.80~3.76 (m, 1H), 2.65 (t, J=7.6 Hz, 2H), 2.41 (s, 3H), 2.27~2.21(m, 2H), 2.10 (s, 3H), 1.09 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.9, 170.5, 147.9, 147.5, 140.9, 138.2, 134.9, 133.3, 129.6, 128.1, 128.1, 127.9, 125.8, 120.3, 70.7, 68.0, 65.9, 35.3, 34.9, 33.0, 30.0, 22.0, 20.6, 20.5, 15.6, 13.6. HRMS calcd for C26H28O4Na [M+Na]+ 427.1880, found 427.1870.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-5-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3h):无色油状, 147 mg, 产率66%. 1H NMR (CDCl3, 400 MHz) δ: 7.66~7.63 (m, 2H), 7.30~7.26 (m, 3H), 7.22~7.18 (m, 4H), 6.41 (t, J=7.5 Hz, 1H), 5.98 (dd, J=10.2, 1.4 Hz, 1H), 5.89 (ddd, J=10.2, 4.1, 2.1 Hz, 1H), 5.35~5.34 (m, 1H), 4.84~4.82 (m, 1H), 4.14 (qd, J=6.6, 2.3 Hz, 1H), 2.98~2.83 (m, 2H), 2.80~2.69 (m, 2H), 2.66 (t, J=7.7 Hz, 2H), 1.83 (s, 3H), 1.66~1.60 (m, 2H), 1.40~1.34 (m, 2H), 1.30 (d, J=6.8 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.2, 170.9, 148.2, 147.8, 141.2, 138.5, 135.2, 133.6, 129.9, 128.5, 128.4, 128.2, 126.1, 120.6, 71.0, 68.4, 66.3, 35.7, 35.3, 33.3, 30.2, 22.4, 20.9, 15.9, 13.9. HRMS calcd for C29H34O4Na [M+Na]+ 469.2349, found 469.2351.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲氧基苯基)-5-苯基- 2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3i):无色油状, 109 mg, 产率52%. 1H NMR (CDCl3, 400 MHz) δ: 7.72~7.68 (m, 2H), 7.31~7.28 (m, 2H), 7.22~7.18 (m, 3H), 6.91~6.87 (m, 2H), 6.32 (t, J=7.4 Hz, 1H), 5.98 (dd, J=10.3, 1.3 Hz, 1H), 5.87 (ddd, J=10.2, 4.6, 2.4 Hz, 1H), 5.30~5.29 (m, 1H), 4.85~4.82 (m, 1H), 4.11 (qd, J=6.7, 2.5 Hz, 1H), 3.87 (s, 3H), 2.96~2.82 (m, 2H), 2.81~2.71 (m, 2H) 1.85 (s, 3H), 1.28 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.3, 170.9, 163.1, 146.7, 141.2, 138.5, 133.6, 132.2, 130.2, 128.5, 128.5, 126.1, 120.8, 113.4, 70.9, 68.4, 66.6, 55.5, 35.3, 30.1, 20.9, 16.0. HRMS calcd for C26H28O5Na [M+Na]+ 443.1829, found 443.1844.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3j):无色油状, 112 mg, 产率68%. 1H NMR (CDCl3, 400 MHz) δ: 7.83~7.82 (m, 2H), 7.28~7.26 (m, 2H), 5.98 (ddd, J10.3, 3.0, 1.6 Hz, 1H), 5.90~5.82 (m, 2H), 5.07~5.06 (m, 1H), 4.12 (qd, J=4.1, 2.1 Hz, 1H), 3.85~3.79 (m, 1H), 2.43 (s, 3H), 2.09 (s, 3H), 1.96~1.88 (m, 2H), 1.11 (d, J=6.4 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.5, 171.0, 150.8, 149.2, 137.8, 135.6, 133.8, 130.2, 127.8, 120.9, 70.9, 68.7, 66.6, 29.1, 22.0, 21.3, 16.2, 15.4, 13.6. HRMS calcd for C20H24- O4Na [M+Na]+ 351.1567, found 351.1569.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-乙基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3k):无色油状, 118 mg, 产率69%. 1H NMR (CDCl3, 400 MHz) δ: 7.71~7.68 (m, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.35 (t, J=7.7 Hz, 1H), 6.06 (dd, J=10.2, 1.2 Hz, 1H), 5.88 (ddd, J=10.2, 4.6, 2.4 Hz, 1H), 5.38~5.36 (m, 1H), 4.88~4.85 (m, 1H), 4.13 (qd, J=6.8, 2.8 Hz, 1H), 2.71 (q, J=7.6 Hz, 2H), 2.61~2.53 (s, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.25 (d, J=2.6 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.5, 171.0, 150.8, 149.2, 137.8, 135.6, 133.8, 130.2, 127.8, 120.9, 70.9, 68.7, 66.6, 29.1, 22.0, 21.3, 16.2, 15.4, 13.6. HRMS calcd for C21H26O4Na [M+Na]+ 365.1723, found 365.1725.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3l):无色油状, 135 mg, 产率73%. 1H NMR (CDCl3, 400 MHz) δ: 7.69~7.67 (m, 2H), 7.27~7.23 (m, 2H), 6.36 (t, J=7.6 Hz, 1H), 6.06 (dd, J=10.2, 1.3 Hz, 1H), 5.89 (ddd, J=10.2, 4.5, 2.5 Hz, 1H), 5.38~5.36 (m, 1H), 4.88~4.86 (m, 1H), 4.14 (qd, J=6.7, 3.0 Hz, 1H), 2.67 (t, J=7.6 Hz, 2H), 2.61~2.54 (m, 2H), 2.08 (s, 3H), 1.64~1.60 (m, 2H), 1.42~1.34 (m, 2H), 1.30 (d, J=6.8 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.4, 170.8, 150.7, 150.7, 147.8, 137.7, 135.4, 133.7, 130.0, 128.2, 120.7, 70.8, 68.6, 66.5, 35.7, 33.3, 22.4, 21.9, 21.2, 16.1, 14.0, 13.5. HRMS calcd for C23H30O4Na [M+Na]+ 393.2036, found 393.2038.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲氧基苯基)-2-戊烯- 1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3m):无色油状, 110 mg, 产率64%. 1H NMR (CDCl3, 400 MHz) δ: 7.80~7.77 (m, 2H), 6.94~6.90 (m, 2H), 6.26 (t, J=7.6 Hz, 1H), 6.06 (dd, J=10.2, 1.2 Hz, 1H), 5.87 (ddd, J=10.3, 4.1, 2.3 Hz, 1H), 5.32~5.31 (m, 1H), 4.87~4.85 (m, 1H), 4.10 (qd, J=6.5, 3.1 Hz, 1H), 3.86 (s, 3H), 2.58~2.51 (m, 2H), 2.06 (s, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.5, 170.8, 163.0, 148.9, 137.7, 133.5, 132.2, 130.4, 121.0, 113.4, 70.6, 68.7, 66.8, 55.5, 21.8, 21.2, 16.2, 13.6. HRMS calcd for C20H24O5Na [M+Na]+ 367.1516, found 367.1531.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3n):黄色油状, 108 mg, 产率63%. 1H NMR (CDCl3, 400 MHz) δ: 7.68~7.65 (m, 2H), 7.25~7.23 (m, 2H), 6.12~6.10 (m, 1H), 6.07 (dd, J=10.2, 1.3 Hz, 1H), 5.88 (ddd, J=10.2, 4.3, 2.5 Hz, 1H), 5.36~5.34 (m, 1H), 4.88~4.85 (m, 1H), 4.12 (qd, J=6.8, 3.0 Hz, 1H), 3.42~3.33 (m, 1H), 2.42 (s, 3H), 2.07 (s, 3H), 1.29 (d, J=6.8 Hz, 3H), 1.07 (d, J=6.5 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.5, 170.8, 155.3, 142.9, 135.8, 135.2, 133.8, 130.1, 128.9, 120.7, 70.6, 68.6, 66.7, 27.5, 22.5, 22.2, 21.6, 21.2, 16.1. HRMS calcd for C21H26O4Na [M+Na]+ 365.1723, found 365.1725.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-乙基苯基)-5-甲基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3o):黄色油状, 133 mg, 产率72%. 1H NMR (CDCl3, 400 MHz) δ: 7.84 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.98 (ddd, J=10.3, 3.2, 1.8 Hz, 1H), 5.91~5.86 (m, 2H), 5.07 (br, 1H), 5.00 (dd, J=7.7, 1.8 Hz, 1H), 3.86~3.79 (m, 1H), 2.72 (q, J=7.6 Hz, 2H), 2.09 (s, 3H), 1.91~1.77 (m, 2H), 1.68~1.61 (m, 1H), 1.27 (t, J=7.6 Hz, 3H), 1.11 (d, J=6.2 Hz, 3H), 0.82 (t, J=6.7 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 198.5, 170.6, 150.4, 139.2, 135.0, 133.7, 130.0, 129.5 128.1, 126.5, 73.2, 70.4, 66.7, 38.5, 29.0, 28.5, 22.4, 22.1, 17.5, 15.1. HRMS calcd for C23H30O4Na [M+Na]+ 393.2036, found 393.2034.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-丁基苯基)-5-甲基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3p):无色油状, 139 mg, 产率70%. 1H NMR (CDCl3, 400 MHz) δ: 7.70~7.68 (m, 2H), 7.25~7.23 (m, 2H), 6.39 (t, J=7.6 Hz, 1H), 6.06 (dd, J=10.3, 1.2 Hz, 1H), 5.88 (ddd, J=10.2, 4.2, 2.5 Hz, 1H), 5.37~5.35 (m, 1H), 4.88~4.86 (m, 1H), 4.14 (qd, J=6.7, 2.7 Hz, 1H), 2.66 (t, J=7.7 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.76~1.68 (m, 1H), 1.64~1.59 (m, 2H), 1.42~1.34 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 0.96~0.91 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ: 197.4, 170.8, 148.6, 147.8, 138.6, 135.4, 133.8, 129.9, 128.2, 120.5, 70.9, 68.5, 66.2, 37.2, 35.6, 33.3, 28.6, 22.7, 22.6, 22.3, 21.2, 16.0, 13.9. HRMS calcd for C23H30O4Na [M+Na]+ 421.2349, found 421.2351.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(3-氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3q):黄色油状, 149 mg, 产率86%. 1H NMR (CDCl3, 400 MHz) δ: 7.71 (dt, J=7.7, 1.2 Hz, 1H), 7.61 (ddd, J=9.3, 2.6, 1.5 Hz, 1H), 7.49~7.44 (m, 1H), 7.31~7.26 (m, 1H), 5.97 (ddd, J=10.3, 2.8, 1.5 Hz, 1H), 5.90 (dt, J=10.3, 2.0 Hz, 1H), 5.68 (dd, J=10.7, 1.2 Hz, 1H), 5.03~5.01 (m, 1H), 4.99 (dq, J=7.3, 3.7, 2.2 Hz, 1H), 3.82~3.75 (m, 1H), 2.27~2.15 (m, 1H), 2.08 (m, 3H), 1.12 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 197.4, 170.5, 162.8 (d, JCF=247.0 Hz), 142.1, 139.7 (d, JCF=6.0 Hz), 135.9, 130.19 (d, JCF=8.0 Hz), 129.8, 126.6, 125.0, 120.5, 120.6, 120.3 115.7 (d, JCF=22.0 Hz), 72.9, 70.2, 67.0, 29.1, 22.6, 22.4, 21.1, 17.4. HRMS calcd for C20H25FO4 [M+H]+ 347.1653, found 347.1650.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(4-氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3r):黄色油状, 145 mg, 产率84%. 1H NMR (CDCl3, 400 MHz) δ: 7.82~7.77 (m, 2H), 7.15~7.09 (m, 2H), 6.10~6.04 (m, 2H), 5.89 (ddd, J=10.0, 4.4, 2.4 Hz, 1H), 5.34~5.32 (m, 1H), 4.87~4.85 (m, 1H), 4.11 (qd, J=6.7, 2.9 Hz, 1H), 3.42~3.32 (m, 1H), 2.07 (s, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.6, 171.1, 165.5 (d, JCF=252.0 Hz), 155.7, 136.0, 134.4 (d, JCF=3.0 Hz), 133.9, 132.6 (d, JCF=9.0 Hz), 121.1, 115.6 (d, JCF=22.0 Hz), 71.0, 68.7, 66.8, 27.8, 22.8, 22.5, 21.5, 16.3. HRMS calcd for C20H23FO4Na [M+Na]+ 369.1473, found 369.1478.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(3, 5-二氟苯基)-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3s):无色油状, 168 mg, 产率92%. 1H NMR (CDCl3, 400 MHz) δ: 7.46~7.40 (m, 2H), 7.06~7.01 (m, 1H), 5.98~5.89 (m, 2H), 5.70 (dd, J=10.7, 1.2 Hz, 1H), 5.00~4.96 (m, 2H), 3.80~3.74 (m, 1H), 2.22~2.16 (m, 1H), 2.08 (s, 3H), 1.13 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.1, 170.5, 163.1 (dd, JCF=249.0, 10.0 Hz), 140.7 (t, JCF=7.0 Hz), 135.6, 129.6, 126.7, 115.3 (dd, JCF=19.0, 7.0 Hz), 111.95, 108.6 (t, JCF=26.0 Hz), 72.7, 70.0, 67.1, 29.2, 22.6, 22.3, 21.1, 18.2, 17.3. HRMS calcd for C20H23F2O4 [M+H]+ 365.1559, found 365.1567.

    (2S, 3R, 6R)-2-甲基-6-((Z)-4-甲基-1-(4-氟苯基)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3t):无色油状, 148 mg, 产率82%. 1H NMR (CDCl3, 400 MHz) δ: 7.82~7.77 (m, 2H), 7.14~7.09 (m, 2H), 6.35 (t, J=7.6Hz, 1H), 6.04 (dd, J=10.3, 1.2 Hz, 1H), 5.89 (ddd, J=10.0, 4.4, 2.2 Hz, 1H), 5.35~5.33 (m, 1H), 4.88~4.85 (m, 1H), 4.13 (qd, J=6.8, 2.8 Hz, 1H), 2.47~2.44 (m, 2H), 2.08 (s, 3H), 1.76~1.66 (m, 1H), 1.31 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 196.1, 170.8, 165.2 (d, JCF=253.0 Hz), 148.4, 138.8, 134.2 (d, JCF=3.0 Hz), 133.5, 132.2 (d, JCF=9.0 Hz), 120.9, 115.3 (d, JCF=22.0 Hz), 71.0, 68.4, 66.2, 37.3, 28.7, 22.7, 22.6, 21.2, 16.0. HRMS calcd for C21H25FO4Na [M+Na]+ 383.1629, found 383.1628.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(3-基噻吩)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3u):黄色油状, 114 mg, 产率68%. 1H NMR (CDCl3, 400 MHz) δ: 8.01 (dd, J=2.9, 1.2 Hz, 1H), 7.55 (dd, J=5.1, 1.2 Hz, 1H), 7.33 (dd, J=5.1, 3.0 Hz, 1H), 5.97 (ddd, J=10.3, 2.9, 1.6 Hz, 1H), 5.88 (dt, J=10.3, 2.1 Hz, 1H), 5.85~5.81 (m, 1H), 5.06 (br, 1H), 5.00 (dq, J=7.5, 2.2 Hz, 1H), 3.83~3.76 (m, 1H), 2.08 (s, 3H) 2.02~1.92 (m, 2H), 1.44~1.34 (m, 2H), 1.10 (d, J=6.4 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 192.5, 170.6, 142.9, 139.6, 134.7, 134.3, 130.0, 127.2, 126.6, 126.5, 73.0, 70.4, 66.9, 31.8, 22.5, 21.2, 17.5, 13.7. HRMS calcd for C18H23O4S [M+H]+ 357.1132, found 357.1132.

    (2S, 3R, 6R)-2-甲基-6-((Z)-2-辛烯-4-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3v):黄色油状, 113 mg, 产率81%. 1H NMR (CDCl3, 400 MHz) δ: 5.94~5.83 (m, 3H), 5.00~4.97 (m, 2H), 3.76~3.70 (m, 1H), 2.71~2.55 (m, 2H), 2.08 (s, 3H), 1.85 (dd, J=7.2, 1.1 Hz, 3H), 1.65~1.57 (m, 2H), 1.40~1.31 (m, 2H), 1.18 (d, J=6.4 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 206.1, 170.6, 141.0, 133.2, 130.4, 126.2, 71.7, 70.2, 66.8, 42.3, 25.7, 22.4, 21.1, 17.6, 15.3, 13.9. HRMS calcd for C16H25O4 [M+H]+ 281.1747, found 281.1751.

    (2S, 3R, 6R)-2-甲基-6-((Z)-2-十二烯-4-酮)-3, 6-二氢- 2H-吡喃-3-基乙酸酯(3w):无色油状, 124 mg, 产率74%. 1H NMR (CDCl3, 400 MHz) δ: 5.94~5.81 (m, 3H), 5.00~4.97 (m, 2H), 3.76~3.69 (m, 1H), 2.70~2.54 (m, 2H), 2.08 (s, 3H), 1.85 (dd, J=7.2, 1.0 Hz, 3H), 1.66~1.58 (m, 2H), 1.32~1.24 (m, 10H), 1.18 (d, J=6.4 Hz, 3H), 0.89~0.86 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 206.1, 170.5, 141.0, 133.2, 130.4, 126.2, 71.7, 70.3, 66.7, 42.6, 31.8, 29.4, 29.3, 29.2, 23.6, 22.6, 21.1, 17.6, 15.3, 14.1. HRMS calcd for C20H33O4 [M+H]+ 337.2373, found 337.2378.

    (2S, 3R, 6R)-2-甲基-6-((Z)-2-甲基-3-壬烯-5-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3x):黄色油状, 117 mg, 产率76%. 1H NMR (CDCl3, 400 MHz) δ: 5.94~5.86 (m, 2H), 5.47 (dd, J=10.2, 1.1 Hz, 1H), 5.00~4.94 (m, 2H), 3.75~3.69 (m, 1H), 2.70~2.53 (m, 3H), 2.08 (s, 3H), 1.64~1.56 (m, 3H), 1.39~1.32 (m, 2H), 1.18 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 206.8, 170.9, 144.5, 138.5, 130.7, 126.5, 72.2, 70.5, 67.0, 43.0, 28.9, 26.0, 23.3, 23.2, 22.7, 21.4, 17.9, 14.2. HRMS calcd for C18H29O4 [M+H]+ 309.2060, found 309.2063.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-(4-甲基苯基)-1-庚烯-3-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(3y):黄色油状, 116 mg, 产率65%. 1H NMR (CDCl3, 400 MHz) δ: 7.14~7.09 (m, 4H), 6.69 (s, 1H), 6.01 (ddd, J=10.3, 2.9, 1.5 Hz, 1H), 5.95 (dt, J=10.3, 2.0 Hz, 1H), 5.14~5.12 (m, 1H), 5.04 (dq, J=7.2, 2.4 Hz, 1H), 3.88~3.81 (m, 1H), 2.35 (s, 3H), 2.33~2.23 (m, 2H), 2.12 (s, 3H), 1.59~1.55 (m, 2H), 1.54~1.42 (m, 2H), 1.22 (d, J=6.3 Hz, 3H), 0.79 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 209.4, 170.5, 141.3, 138.6, 132.4, 132.4, 130.2, 129.2, 128.6, 126.6, 73.1, 70.4, 67.0, 43.3, 25.7, 22.0, 21.3, 21.2, 17.7, 13.8. HRMS calcd for C22H29O4 [M+H]+ 357.2060, found 357.2066.

    3.2.2   化合物4的合成

    在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1 (0.5 mmol), 炔丙酯2 (0.5 mmol), CH3NO2 (5 mL), 室温搅拌10 min后, 迅速加入Ph3PAuCl (12.3 mg, 5 mol%)和AgSbF6 (6.5 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.硅胶快速色谱法(石油醚/乙酸乙酯, V:V=10:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物4.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-苯基乙酸酯(4ba):无色油状, 143 mg, 产率76%. 1H NMR (CDCl3, 400 MHz) δ: 8.05~8.03 (m, 2H), 7.97~7.94 (m, 2H), 7.61~7.56 (m, 2H), 7.51~7.44 (m, 4H), 6.04~6.03 (m, 1H), 5.92 (td, J=7.7, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 3.49 (d, J=5.4 Hz, 1H), 2.05~1.88 (m, 2H), 1.19 (d, J=6.3 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.8, 166.1, 137.9, 137.5, 136.7, 133.5, 133.2, 130.3, 130.1, 129.7, 129.3, 128.7, 128.4, 126.5, 73.1, 70.8, 67.2, 23.3, 17.6, 13.7. HRMS calcd for C24H24O4Na [M+Na]+ 399.1567, found 399.1566.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-苯基乙酸酯(4bb):无色油状, 148 mg, 产率73%. 1H NMR (CDCl3, 400 MHz) δ: 8.05~8.02 (m, 2H), 7.96~7.93 (m, 2H), 7.61~7.56 (m, 2H), 7.50~7.43 (m, 4H), 6.07~6.03 (m, 2H), 5.97 (td, J=7.0, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 1.93~1.77 (m, 2H), 1.72~1.65 (m, 1H), 1.19 (d, J=6.3 Hz, 3H), 0.84 (t, J=6.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 198.9, 166.1, 139.2, 137.4, 134.4, 133.4, 133.2, 130.3, 130.1, 129.7, 129.3, 128.7, 128.4, 126.5, 73.2, 70.8, 67.1, 38.5, 28.6, 22.4, 22.2, 17.6. HRMS calcd for C26H28O4 Na [M+Na]+ 427.1880, found 427.1881.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(2-氯苯基)-乙酸酯(4ca):无色油状, 162 mg, 产率74%. 1H NMR (CDCl3, 400 MHz) δ: 7.93~7.91 (m, 2H), 7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.60~7.55 (m, 1H), 7.49~7.41 (m, 4H), 7.35~7.29 (m, 1H), 6.08~6.03 (m, 2H), 5.95 (td, J=7.1, 1.3 Hz, 1H), 5.28~5.26 (m, 1H), 5.13 (br, 1H), 4.04~3.97 (m, 1H), 1.90~1.75 (m, 2H), 1.69~1.63 (m, 1H), 1.22 (d, J=6.3 Hz, 3H), 0.82 (t, J=6.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 198.8, 165.4, 139.1, 137.4, 134.5, 133.7, 133.4, 132.7, 131.4, 131.1, 130.7, 130.1, 129.3, 128.7, 126.6, 126.0, 73.1, 71.5, 67.0, 38.5, 28.5, 22.4, 22.2, 17.7. HRMS calcd for C26H27ClO4Na [M+Na]+ 461.1490, found 461.1491.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(3-氯苯基)-乙酸酯(4da):无色油状, 164 mg, 产率75%. 1H NMR (CDCl3, 400 MHz) δ: 8.04 (t, J=1.9 Hz, 1H), 7.95 (dt, J=7.8, 1.4 Hz, 1H), 7.78~7.76 (m, 2H), 7.56~7.52 (m, 2H), 7.46~7.42 (m, 2H), 7.37 (t, J=7.9 Hz, 1H), 6.42 (t, J=7.4 Hz, 1H), 6.15 (dd, J=10.2, 1.8 Hz 1H), 6.01 (ddd, J=10.2, 4.7, 2.5 Hz, 1H), 5.46~5.44 (m, 1H), 5.12~5.10 (m, 1H), 4.31 (qd, J=7.1, 2.4 Hz, 1H), 2.57~2.44 (m, 2H), 1.76~1.69 (m, 1H), 1.39 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 197.6, 165.2, 149.2, 138.7, 138.0, 134.5, 133.1, 132.2, 131.9, 129.8, 129.7, 129.7, 128.2, 128.0, 120.4, 71.2, 69.4, 66.0, 37.3, 28.7, 22.6, 22.5, 16.0. HRMS calcd for C26H27ClO4Na [M+Na]+ 461.1490, found 461.1491.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(2-氟苯基)-乙酸酯(4ea):无色油状, 160 mg, 产率76%. 1H NMR (CDCl3, 400 MHz) δ: 7.94~7.89 (m, 3H), 7.60~7.53 (m, 2H), 7.50~7.49 (m, 2H), 7.22~7.13 (m, 2H), 6.07~6.01 (m, 2H), 5.96 (td, J=7.0, 1.2 Hz, 1H), 5.27~5.24 (m, 1H), 5.13 (br, 1H), 4.03~3.97 (m, 1H), 1.92~1.75 (m, 2H), 1.69~1.62 (m, 1H), 1.20 (d, J=6.4 Hz, 3H), 0.83 (m, J=6.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 198.9, 164.0, 164.0, 162.0 (d, JCF=259.0 Hz), 139.1, 137.4, 134.7 (d, JCF=9.0 Hz), 134.5, 133.4, 132.1, 130.4, 129.3, 128.7, 126.4, 124.0 (d, JCF=4.0 Hz), 118.8, 118.7, 117.0 (d, JCF=22.0 Hz), 73.2, 71.4, 66.9, 38.5, 28.6, 22.4, 22.2, 17.6. HRMS calcd for C26H27FO4Na [M+Na]+ 445.1786, found 445.1784.

    (2S, 3R, 6R)-2-甲基-6-((Z)-5-甲基-1-苯基-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-(4-氟苯基)-乙酸酯(4fa):无色油状, 165 mg, 产率78%. 1H NMR (CDCl3, 400 MHz) δ: 8.09~8.06 (m, 2H), 7.78~7.76 (m, 2H), 7.56~7.52 (m, 1H), 7.46~7.42 (m, 2H), 7.12~7.6 (m, 2H), 6.40 (t, J=7.4 Hz, 1H), 6.14 (dd, J=10.3, 1.9 Hz, 1H), 6.01 (ddd, J=10.3, 4.8, 2.5 Hz, 1H), 5.45~5.44 (m, 1H), 5.11~5.09 (m, 1H), 4.30 (qd, J=6.8, 2.4 Hz, 1H), 2.57~2.43 (m, 2H), 1.75~1.66 (m, 1H), 1.39 (d, J=6.8 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 197.6, 165.8 (d, JCF=253.0 Hz), 165.4, 148.8, 138.8, 138.1, 134.2, 132.4 (d, JCF=9.0 Hz), 132.2, 129.7, 128.2, 126.3 (d, JCF=3.0 Hz), 120.7, 115.5 (d, JCF=22.0 Hz), 71.2, 69.1, 66.0, 37.3, 28.7, 22.6, 22.5, 16.1. HRMS calcd for C26H27- FO4Na [M+Na]+ 445.1786, found 445.1784.

    3.2.3   化合物5a~5b的合成

    在25 mL的Schlenk管内, 依次加入L-岩藻烯糖1g (107 mg, 0.5 mmol), 炔丙酯2 (0.5 mmol)以及CH3NO2 (5 mL).室温搅拌10 min后, 迅速加入Ph3PAuCl (12.3 mg, 5 mol%)和AgSbF6 (6.5 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.硅胶快速色谱法(PE:EtOAc, V:V=20:1)纯化残余物, 得到C-乙烯基岩藻糖苷衍生物5.

    (2S, 3S, 6R)-2-甲基-6-((Z)-1-苯基-2-戊烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(5a):无色油状, 151 mg, 产率96%. 1H NMR (CDCl3, 400 MHz) δ: 7.91~7.88 (m, 2H), 7.61~7.57 (m, 1H), 7.50~7.46 (m, 2H), 6.17~6.07 (m, 2H), 5.80 (td, J=7.7, 1.3 Hz, 1H), 5.20~5.19 (m, 1H), 5.00 (dd, J=4.8, 2.4 Hz, 1H), 4.06 (qd, J=6.5, 2.4 Hz, 1H), 2.09 (s, 3H), 1.98~1.90 (m, 2H) 1.08 (d, J=6.6 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.7, 170.9, 137.5, 137.4, 136.7, 133.4, 132.1, 129.1, 128.7, 124.7, 73.7, 66.2, 66.0, 23.2, 20.9, 16.0, 13.7. HRMS calcd for C19H22O4Na [M+Na]+ 337.1410, found 337.1412.

    (2S, 3S, 6R)-2-甲基-6-((Z)-5-甲基-1-(4-丁基苯基)-2-己烯-1-酮)-3, 6-二氢-2H-吡喃-3-基乙酸酯(5b):无色油状, 183 mg, 产率92%. 1H NMR (CDCl3, 400 MHz) δ: 7.73~7.71 (m, 2H), 7.26~7.24 (m, 2H), 6.17 (t, J=7.5 Hz, 1H), 6.09 (dd, J=10.1, 2.9 Hz, 1H), 5.95 (ddd, J=10.2, 4.6, 2.4 Hz, 1H), 5.39 (br, 1H), 5.14~5.12 (m, 1H), 4.22 (qd, J=6.6, 3.1 Hz, 1H), 2.67 (t, J=7.7 Hz, 2H), 2.34 (t, J=7.2 Hz, 2H), 1.77~1.70 (m, 1H), 1.66~1.60 (m, 2H), 1.42~1.32 (m, 2H), 1.16 (d, J=6.5 Hz, 3H), 0.96~0.92 (m, 9H); 13C NMR (CDCl3, 100 MHz) δ: 197.3, 170.8, 148.4, 144.5, 139.5, 135.5, 132.6, 130.1, 128.4, 122.7, 69.0, 68.0, 66.8, 37.3, 35.7, 33.3, 29.7, 28.6, 22.6, 22.5, 22.4, 21.0, 15.5, 13.9. HRMS calcd for C25H34O4Na [M+Na]+ 421.2349, found 421.2341.

    3.2.4   化合物3a-18O的合成

    在25 mL的Schlenk管内, 依次加入L-鼠李烯糖1a (54 mg, 0.25 mmol), 炔丙酯2a-18O (54 mg, 0.25 mmol), 以及CH3NO2 (3 mL).室温搅拌10 min后, 快速加入Ph3PAuCl (6 mg, 5 mol%)和AgSbF6 (3 mg, 5 mol%).室温下搅拌6 h, TLC检测反应完全.用砂芯漏斗过滤, 减压浓缩除去溶剂.通过硅胶快速色谱法(石油醚/乙酸乙酯, V:V=20:1)纯化残余物, 得到C-乙烯基鼠李糖苷衍生物3a-18O.

    (2S, 3R, 6R)-2-甲基-6-((Z)-1-苯基-2-己烯-1-(酮- 18O))-3, 6-二氢-2H-吡喃-3-基乙酸酯(3a-18O):无色油状, 65 mg, 产率79%. 1H NMR (CDCl3, 400 MHz) δ: 7.93~7.90 (m, 2H), 7.60~7.56 (m, 1H), 7.49~7.46 (m, 2H), 5.98 (ddd, J=10.3, 2.9, 1.6 Hz, 1H), 5.91~5.87 (m, 2H), 5.08 (br, 1H), 5.00 (dq, J=7.6, 2.2 Hz, 1H), 3.85~3.79 (m, 1H), 2.09 (s, 3H), 1.95~1.86 (m, 2H), 1.42~1.34 (m, 2H), 1.11 (d, J=6.3 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ: 198.8, 198.8, 170.5, 138.6, 137.5, 135.2, 133.4, 130.1, 129.2, 128.6, 126.6, 73.1, 70.4, 66.9, 31.7, 29.7, 22.4, 21.2, 17.5, 13.7. HRMS calcd for C20H24O318ONa [M+Na]+ 353.1609, found 353.1610.

    辅助材料(Supporting Information) 化合物3, 4, 5的核磁谱图, 化合物3g (CCDC 1965665)的单晶结构数据.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.


    1. [1]

      (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077.
      (b) Chen, C. L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128, 13696.
      (c) Štambaský, J.; Hocek, M.; Kocovský, P. Chem. Rev. 2009, 109, 6729.
      (d) Kitamura, K.; Ando, Y.; Matsumoto, T.; Suzuki, K. Chem. Rev. 2018, 118, 1495.
      (e) Liao, H. Z; Ma, J.; Yao, H.; Liu, X. W. Org. Biomol. Chem. 2018, 16, 1791.
      (f) Norsikian, S.; Tresse, C.; François-Eude, M.; Jeanne-Julien, L.; Masson, G.; Servajean, V.; Genta-Jouve, G.; Beau, J. M.; Roull, E. Angew. Chem., Int. Ed. 2020, 59, 6612.
      (g) Kitamura, K.; Ando, Y.; Matsumoto, T.; Suzuki, K. Chem. Rev. 2018, 118, 1495.

    2. [2]

      (a) Hassanzadeh, A.; Gorry, P. A.; Morris, G. A.; Barber, J. J. Med. Chem. 2006, 49, 6334.
      (b) Kim, B. G.; Kim, H. J.; Ahn, J. H. J. Agric. Food. Chem. 2012, 60, 11143.
      (c) Bhattarai, B.; Nagorny, P. Org. Lett. 2018, 20, 154.
      (d) Chauvin, A.; Nepogodiev, S.; Field, R. J. Org. Chem. 2005, 70, 960.
      (e) Urabe, D.; Nakagawa, Y.; Mukai, K.; Fukushima, K.; Aoki, N.; Itoh, H.; Nagatomo, M.; Inoue, M. J. Org. Chem. 2018, 83, 13888.
      (f) Lee, H. S.; Kim, M. J. J. Agric. Food. Chem. 2002, 50, 1840.
      (g) Khatri, H. R.; Bhattarai, B.; Kaplan, W.; Li, Z.; Long, M. J. C.; Aye, Y.; Nagorny, P. J. Am. Chem. Soc. 2019, 141, 4849.
      (h) Crich, D.; Li, H. J. Org. Chem. 2002, 67, 4640.
      (i) Ashraf Shalaby, M.; Fronczek, F. R.; Younathan, E. S. Carbohydr. Res. 1994, 258, 267

    3. [3]

      (a) Chen, C. L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128, 13696.
      (b) Tius, M. A.; Gu, X.; Gomez-Galeno, J. J. Am. Chem. Soc. 1990, 112, 8188.
      (c) Liao, H. Z; Ma, J.; Yao, H.; Liu, X. W. Org. Biomol. Chem. 2018, 16, 1791.

    4. [4]

      (a) Cai, X.; Ng, K.; Panesar, H.; Moon, S. J.; Paredes, M.; Ishida, K.; Hertweck, C.; Minehan, T. G. Org. Lett. 2014, 16, 2962.
      (b) Liao, H. Z; Ma, J.; Yao, H.; Liu, X. W. Org. Biomol. Chem. 2018, 16, 1791.

    5. [5]

      Szeja, W.; Grynkiewicz, G.; Bieg, T.; Swierk, P.; Byczek, A.; Papaj, K.; Kitel, R.; Rusin, A. Molecules 2014, 19, 7072. 

    6. [6]

      (a) Gong, H.; Sinisi, R.; Gagne, M. R. J. Am. Chem. Soc. 2007, 129, 1908.
      (b) Gong, H.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 12177.
      (c) Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem., Int. Ed. 2010, 49, 7274.
      (d) Nicolas, L.; Angibaud, P.; Stansfield, I.; Bonnet, P.; Meerpoel, L.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2012, 51, 11101.
      (e) Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem., Int. Ed. 2012, 51, 4140.
      (f) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc. 2014, 136, 17645.
      (g) Zhu, F.; Rourke, M. J.; Yang, T.; Rodriguez, J.; Walczak, M. A. J. Am. Chem. Soc. 2016, 138, 1204.
      (h) Adak, L.; Kawamura, S.; Toma, G.; Takenaka, T.; Isozaki, K.; Takaya, H.; Orita, A.; Li, H. C.; Shing, T. K. M.; Nakamura, M. J. Am. Chem. Soc. 2017, 139, 10693.

    7. [7]

      (a) Koppolu, S. R.; Niddana, R.; Balamurugan, R. Org. Biomol. Chem. 2015, 13, 5094.
      (b) Wang, Y.; Liu, M.; Liu, L.; Xia, J. H.; Du, Y. G.; Sun, J. S. J. Org. Chem. 2018, 83, 4111.

    8. [8]

      (a) Bolitt, V.; Mioskowski, C.; Kollah, R. O.; Manna, S.; Rajapaksa, D.; Falck, J. R. J. Am. Chem. Soc. 1991, 113, 6320.
      (b) Fuganti, C.; Serra, S. Synlett 1999, 1999, 1241.
      (c) Kulkarni, S. S.; Gervay-Hague, J. Org. Lett. 2006, 8, 5765.
      (d) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9, 1121.
      (e) Snajdr, I.; Parkan, K.; Hessler, F.; Kotora, M. Beilstein J. Org. Chem. 2015, 11, 1392.

    9. [9]

      (a) Li, X.; Chen, G.; Garcia-Navarro, R.; Franck, R. W.; Tsuji, M. Immunology 2009, 127, 216.
      (b) Yao, Y.; Xiong, C. P.; Zhong, y. L.; Bian, G. W.; Huang, N. Y.; Wang, L.; Zou, K. Adv. Synth. Catal. 2019, 5 1012.

    10. [10]

      Bai, Y.; Leow, M.; Zeng, J.; Liu, X.-W. Org. Lett. 2011, 13, 5648. doi: 10.1021/ol202368n

    11. [11]

      Tatina, M.; Kusunuru, A. K.; Yousuf, S. K.; Mukherjee, D. Chem. Commun. 2013, 49, 11409. doi: 10.1039/c3cc46914j

    12. [12]

      (a) Sharma, B. M.; Rathod, J.; Gonnade, R. G.; Kumar, P. J. Org. Chem. 2018, 83, 9353.
      (b) Ruengsangtongkul, S.; Chaisan, N.; Thongsornkleeb, C.; Tummatorn, J. Org. Lett. 2019, 21, 2514.

    13. [13]

      Veryser, C.; Steurs, G.; Meervelt, L. V.; Borggraeve, W. M. Adv. Synth. Catal. 2017, 359, 1271. doi: 10.1002/adsc.201601388

    14. [14]

      Xiao, Q.; Zheng, F.; Tang, Q.; Wu, J. J.; Xie, J.; Huang, H. D.; Yang, X. B.; Hann, S. S. Cell Physiol. Biochem. 2018, 49, 1615. doi: 10.1159/000493497

    15. [15]

      (a) Xu, Y.; Wang, W. J.; Cai, Y.; Yang, X.; Wang, P. G.; Zhao, W. RSC Adv. 2014, 4, 46662.
      (b) Gagarinov, I. A.; Fang, T.; Liu, L.; Srivastava, A. D.; Boons, G. J. Org. Lett. 2015, 17, 928.
      (c) Suzuki, K.; Sulikowski, G. A.; Friesen, R. W.; Danishefsk, S. J. J. Am. Chem. Soc. 1990, 112, 8895.
      (d) Wang, J.; Deng, C.; Zhang, Q.; Chai, Y. Org. Lett. 2019, 21, 1103.

    16. [16]

      (a) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem., Int. Ed. 2015, 54, 12134.
      (b) Reddy, V.; Vijaya, A. R. Org. Lett. 2015, 17, 3390.
      (c) Chu, W. D.; Zhang, L. F.; Bao, X.; Zhao, X. H.; Zeng, C.; Du, J. Y.; Zhang, G. B.; Wang, F. X.; Ma, X. Y.; Fan, C. A. Angew. Chem., Int. Ed. 2013, 52, 9229.
      (d) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2014, 16, 1176.

  • 图 1  化合物3g的晶体结构

    Figure 1  X-ray single crystal structure of 3g

    图式 1  可能的反应机理

    Scheme 1  Possible reaction mechanism

    图 2  化合物3i的胃癌细胞毒活性

    Figure 2  Cytotoxities against HGC-27 cells of compound 3i

    表 1  模型反应条件优化a

    Table 1.  Optimization of reaction conditions for the model reaction

    Entry Catalyst Solvent Time/h Yieldb/%
    1 Au2O3 CH2Cl2 24 N.D.
    2 TiCl4 CH2Cl2 24 N.D.
    3 Ni(CO)4 CH2Cl2 24 N.D.
    4 PdCl2 CH2Cl2 24 N.D.
    5 Ag2CO3 CH2Cl2 24 N.D.
    6 AuCl3 CH2Cl2 6 21
    7 AuBr3 CH2Cl2 6 12
    8 AuCl CH2Cl2 6 31
    9 Ph3PAuCl CH2Cl2 24 N.D.
    10 AgSbF6 CH2Cl2 24 N.D.
    11 Au(CO)Cl/AgSbF6 CH2Cl2 6 24
    12 Ph3PAuCl/AgSbF6 CH2Cl2 6 58
    13 Ph3PAuNTf2/AgSbF6 CH2Cl2 6 42
    14 Ph3PAuCl/AgNO3 CH2Cl2 6 28
    15 Ph3PAuCl/CH3CO2Ag CH2Cl2 6 37
    16 Ph3PAuCl/Ag2CO3 CH2Cl2 6 45
    17 Ph3PAuCl/Ag3PO4 CH2Cl2 6 48
    18 (C5H5N)AuCl3/AgSbF6 CH2Cl2 6 46
    19 Ph3PAuCl/AgSbF6 DMF 6 N.D.
    20 Ph3PAuCl/AgSbF6 CHCl3 6 36
    21 Ph3PAuCl/AgSbF6 Toluene 6 25
    22 Ph3PAuCl/AgSbF6 CH3NO2 6 78
    23 Ph3PAuCl/AgSbF6 CH3CN 6 12
    24 Ph3PAuCl/AgSbF6 EtOAc 6 N.D.
    aGeneral conditions: catalyst (5 mol%) was added into the mixture of 1a (107 mg, 0.5 mmol) and 2a (113 mg, 0.5 mmol) in corresponding solvent (5 mL). b Isolated yield. N.D.=not detected.
    下载: 导出CSV

    表 2  C-乙烯基鼠李糖苷衍生物的底物拓展

    Table 2.  Substrate scope for C--vinyl-rhamnopyranoside derivatives

    下载: 导出CSV

    表 3  C-乙烯基鼠李糖苷衍生物的底物扩展

    Table 3.  Substrate expansion of C-vinyl-rhamnopyranoside derivatives

    Entry R1 (1) R2 Yield/% (4)
    1 Ph (1b) Et 76 (4ba)
    2 Ph (1b) iBu 73 (4bb)
    3 2-ClC6H4 (1c) iBu 74 (4ca)
    4 3-ClC6H4 (1d) iBu 75 (4da)
    5 2-FC6H4 (1e) iBu 76 (4ea)
    6 4-FC6H4 (1f) iBu 78 (4fa)
    下载: 导出CSV

    表 4  目标化合物的细胞毒活性

    Table 4.  Cytotoxic activity of target compounds

    化合物 IC50值/(μmol•L1)
    胃癌细胞 宫颈癌细胞 肝癌细胞 人胃粘膜细胞
    3a~3h >100 >100 >100 >100
    3i 18.29 >100 >100 >100
    3j~3o >100 >100 >100 >100
    3p 82.91 >100 >100 >100
    3q~3y >100 >100 >100 >100
    4ba >100 >100 >100 >100
    4bb 90.21 >100 >100 >100
    4ca~4fa >100 >100 >100 >100
    5a~5b >100 >100 >100 >100
    下载: 导出CSV
  • 加载中
计量
  • PDF下载量:  0
  • 文章访问数:  369
  • HTML全文浏览量:  20
文章相关
  • 发布日期:  2020-07-01
  • 收稿日期:  2020-03-14
  • 修回日期:  2020-04-19
  • 网络出版日期:  2020-04-23
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章