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多组分反应合成紫杉醇侧链及其在合成紫杉醇衍生物中的应用

盛家骏 ,  于雅楠 ,  王信 ,  钱宇 ,  符立梧 ,  赵芸 ,  马明亮 ,  胡文浩

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引用本文: 盛家骏, 于雅楠, 王信, 钱宇, 符立梧, 赵芸, 马明亮, 胡文浩. 多组分反应合成紫杉醇侧链及其在合成紫杉醇衍生物中的应用[J]. 有机化学, 2019, 39(2): 377-389. doi: 10.6023/cjoc201806031 shu
Citation:  Sheng Jiajun, Yu Ya'nan, Wang Xin, Qian Yu, Fu Liwu, Zhao Yun, Ma Mingliang, Hu Wenhao. Synthesis of Paclitaxel Side Chain via Multi-Component Reaction and Its Application to the Synthesis of Paclitaxel Analogues[J]. Chinese Journal of Organic Chemistry, 2019, 39(2): 377-389. doi: 10.6023/cjoc201806031 shu

多组分反应合成紫杉醇侧链及其在合成紫杉醇衍生物中的应用

  • a.

    华东师范大学上海分子治疗与新药创制工程技术研究中心 上海 200062

  • b.

    中山大学药学院 广州 510006

  • c.

    中山大学肿瘤防治中心 广州 510060

    • 通讯作者: 马明亮, mlma@brain.ecnu.edu.cn; 胡文浩, huwh9@mail.sysu.edu.cn
  • 基金项目:

    国家自然科学基金（Nos.21572067，21332003）资助项目

摘要: 以水、重氮乙酸酯、芳香醛和芳香胺为原料，在单一催化剂Cu（OTf）2的作用下成功实现了一例基于羟基叶立德捕捉的四组分反应，一步构建了α-羟基-β-氨基酸酯类化合物骨架，并通过进一步的化学转化高效地合成了紫杉醇噁唑烷型侧链.此外，将所得侧链与紫杉醇母核、卡巴他赛母核对接，成功合成了14个紫杉醇衍生物，并在随后的抗肿瘤细胞活性测试中，发现了多个活性优异的新型化合物.将多组分反应方法学与应用相结合，开发了一种高效合成紫杉醇侧链衍生物的方法，并成功地将其应用到紫杉醇衍生物的半合成中，为该类化合物的构效关系研究提供了一种新途径，具有潜在的应用价值.

English

  • 紫杉醇(paclitaxel, 商品名Taxol®)是从太平洋红杉的树皮中提取出来的一种具有抗肿瘤活性二萜类天然产物, 它与其结构改造衍生物多西紫杉醇(docetaxel)和卡巴他赛(cabazitaxel)均是迄今为止发现最有效的广谱抗肿瘤药物之一[1].目前主要用于治疗乳腺癌、卵巢癌等, 还可与顺铂、吉西他滨、阿霉素、曲妥珠单抗等联合用药, 用于治疗非小细胞肺癌、转移性乳腺癌、AIDS (Acquired Immune Deficiency Syndrom)相关的卡式肉瘤等多种癌症[2].然而, 紫杉醇在红豆杉树皮中的含量极低, 仅有0.069%, 从树皮中分离提取不仅无法满足用药需求, 还会对红豆杉造成致命的损伤, 导致其死亡[3].此外, 紫杉醇的化学结构极其复杂, 化学全合成仅停留在实验室水平[4], 因此目前生产紫杉醇的主要方法是由10-去乙酰基巴卡汀Ⅲ (10-DAB)为原料的半合成法(Scheme 1)[5].紫杉醇C-13侧链是半合成路线中至关重要的一个片断, 为了寻找一条便捷高效的合成路线, 多年来全世界各国化学家都付诸了许多努力.该侧链属于α-羟基-β-氨基酸酯类化合物, 对于这一类化合物, Sharpless不对称羟胺化[6]、Sharpless不对称羟基化[7]、环氧或氮杂环丙烷的选择性开环等方法[8]都曾被报道应用于它们的合成中.除此之外, 过渡金属催化的多组分反应包括Mannich型[9]和1, 3-偶极环加成型[10], 也都是合成紫杉醇侧链的有效方法.我们课题组[9a]曾在2010年报道了一例由醋酸铑与手性磷酸共同催化的三组分反应合成紫杉醇侧链的方法, 并在此基础上, 于2018年[10c]发现了一种通过羰基叶立德多组分[3+2]环加成反应一锅法合成紫杉醇侧链的方法.但这两类方法有一个共同的特点, 它们都需要使用手性配体或昂贵的过渡金属催化剂, 这直接导致该类反应在应用上受到了很大的限制.因此, 我们试图寻找一种廉价高效的催化体系来催化该类多组分反应, 并探索使用水这样一种绿色原料代替醇类作为羟基叶立德来源, 在提高原子经济性的同时减少工艺步骤, 使该方法具有一定的应用前景.

    图式 1

    图式 1.  紫杉醇的半合成
    Scheme 1.  Semi-synthesis of paclitaxel
    下载: 全尺寸图片 幻灯片

    1.   结果与讨论

    循着以上思路, 我们首先对金属催化剂进行了研究, 筛选了价格低廉且催化效果较为优秀的Cu催化剂和Fe催化剂(表 1).同时, 根据课题组以往的经验, 我们用芳香氨3a和苯甲醛(4a)原位制备反应所需亚胺, 进一步减少反应步骤.

    表 1

    表 1  金属催化剂的筛选a
    Table 1.  Selection of metal catalysis
    下载: 导出CSV
    Entry Catalyst x/mol% Yieldb/% drc(syn:anti)
    1 Rh2(OAc)4 2 62 58:42
    2 Cu(OTf)2 10.0 57 44:56
    3 Cu(OTf)2 5.0 58 45:55
    4 Cu(OTf)2 2.0 52 45:55
    5 Cu(OTf)2+p-TsOH 5.0,
    10.0    		 60 38:62
    6 Cu(OTf)2+AgPF6 5.0,
    10.0    		 46 52:48
    7 Cu(CH3CN)4BF4 5.0 43 41:59
    8 Cu(AcAc)2 5.0 — —
    9 CuSO4 5.0 — —
    10 FeCl2 5.0 — —
    11 Fe(OTf)3 5.0 — —
    a The reaction was carried out with aniline 3a (1 equiv.), aldehyde 4a (1.05 equiv.), H2O (3 equiv.) and catalyst (2.0~20.0 mol%) in CH2Cl2 at room temperature with addition of EDA 2 (1.5 equiv.) over 1h. b Isolated yield (two diastereoisomers). c Determined by 1H NMR spectroscopy of the crude reaction mixture.

    如表 1所示, 使用5 mol%的Cu(OTf)2时可以得到更好的结果, 对甲苯磺酸(p-TsOH)共催化可以提升反应收率但是会显著降低反应的非对映选择性, AgPF6共催化虽然可以小幅提升非对映选择性, 但是会降低收率[11].其余的铜催化剂中只有Cu(CH3CN)4BF4能够成功催化该多组分反应, 但是结果不尽人意.除此之外, 我们还筛选了一些其他廉价易得的Fe催化剂, 但是它们都无法使目标多组分反应发生.

    经过上述实验, 虽然在Cu(OTf)2催化下我们得到的顺式构型(syn)的比例相对使用Rh2(OAc)4时有小幅减少, 但是Cu(OTf)2低廉的售价及较好的催化活性使它在放大实验中仍然具有优势, 因此我们仍然决定使用Cu(OTf)2作为该路线的催化剂.

    随后, 进一步筛选了反应溶剂和反应温度(表 2).结果显示, 使用二氯甲烷作溶剂时, 无论升温或降温都会降低反应的收率; 而二氯甲烷以外的其他非质子型溶剂都会在一定程度上降低反应收率或非对映选择性.反应条件筛选完毕后, 将反应规模由50 mg提升至10 g(表 2, Entry 9), 得到的结果与表 1 Entry 3中的数据基本吻合, 这也可以证明该反应体系稳定, 具有放大的前景.

    表 2

    表 2  溶剂与温度的筛选
    Table 2.  Optimization of solvent and temperaturea
    下载: 导出CSV
    Entry Solvent Temp./℃ Yieldb/% drc(syn:anti)
    1 CH2Cl2 0 53 45:55
    2 CH2Cl2 Reflux 47 43:57
    3 THF 25 ＜10 —
    4 CHCl3 25 54 42:58
    5 CH3CN 25 — —
    6 EtOAc 25 45 37:63
    7 Hexane 25 34 46:54
    8 Toluene 25 30 44:56
    9d CH2Cl2 25 56 45:55
    a The reaction was carried out with aniline 3a (1 equiv.), aldehyde 4a (1.05 equiv.), H2O (3 equiv.) and Cu(OTf)2 (5.0 mol%) in the solvent with addition of EDA 2 (1.5 equiv.) over 1 h. b Isolated yield (two diastereoisomers). c Determined by 1H NMR spectroscopy of the crude reaction mixture. d The reaction was carried out on 10 g scale.

    脱除对甲氧基苯基(PMP)保护也是反应路线中相当重要的一步.在该步反应中, 我们选择使用一种温和的氧化剂三氯异氰脲酸(TCCA)以替代通常使用的硝酸铈铵(CAN), 这样不仅避免了OH的保护, 还简化了后处理步骤, 从而大大提高了反应收率[12].最终通过重结晶以60%的收率得到化合物6a, 该步反应同样可顺利放大至10克级(Scheme 2).之后, 将所得到的氨基醇6a在乙酸乙酯和饱和碳酸氢钠水溶液的两相体系中进行苯甲酰化, 所得粗产物经过萃取、分液后再经乙酸乙酯-石油醚体系重结晶, 得到高纯度的白色固体7a.化合物7a在有分水器存在的条件下与对甲氧基苯甲醛二甲缩醛进行环化, 得到化合物8a [13].最后将化合物8a进行碱性水解, 得到目标噁唑烷型侧链9a, 三步反应的总收率可以达到67%.

    图式 2

    图式 2.  噁唑烷型侧链合成路线
    Scheme 2.  Synthesis route of oxazoline type side chain
    下载: 全尺寸图片 幻灯片

    纵观整条合成路线, 每一步反应均成功地放大至10克级, 且操作步骤不需要改变, 得到的结果也与小试时几乎一致.在纯化产物时, 只有在分离非对映异构体syn-5a、anti-5a和分离油状液体8a时使用了柱层析分离, 其余步骤通过简单的重结晶或过滤就可以得到较高纯度的产物.以苯胺为起始原料, 以顺式噁唑烷型侧链9a为终产物计, 5步反应的总收率为10%, 相较先前报道的路线有了很大的提高.

    之后我们选用不同的芳香醛和酰氯对底物进行了拓展.令人惊喜的是, 各步反应均展现出了良好的底物适应性.最终得到了14种不同的紫杉醇噁唑烷型C-13侧链(Scheme 3).

    图式 3

    图式 3.  底物拓展
    Scheme 3.  Scope extension of the substrate
    下载: 全尺寸图片 幻灯片

    在此基础上, 我们成功地将7-三乙基硅基巴卡汀Ⅲ (10, 7-TES Baccatin Ⅲ)和7, 10-二甲氧基-10-去乙酰基巴卡汀Ⅲ (11, 7, 10-dimethoxy-10-DAB)与前述所得的噁唑烷型侧链进行缩合得到紫杉醇衍生物前体12或13, 最后在无水乙醇中进行酸解脱保护, 得到了14种紫杉醇衍生物(Scheme 4).随后我们对几种代表性的肿瘤细胞进行了活性测试(表 3).结果显示, 对于所检测的4种肿瘤细胞, 有多种紫杉醇衍生物的活性优于paclitaxel或cabazitaxel.其中化合物14k和15h表现最为优秀, 对于H460大细胞肺癌和PC9肺腺细胞癌细胞的活性要优于paclitaxel, 对于MG63骨肉瘤和KB口腔表样癌细胞的活性要同时优于paclitaxel和cabazitaxel.这一结果反映了紫杉醇7, 10-位的甲基化取代和侧链3'-位酰胺的杂环取代会对活性产生非常积极的影响, 而3'-位磺酰胺取代会大大降低化合物对肿瘤细胞的活性.

    图式 4

    图式 4.  紫杉醇衍生物的合成
    Scheme 4.  Synthesis of the paclitaxel analogues
    下载: 全尺寸图片 幻灯片

    2.   结论

    研究了通过重氮乙酸乙酯(EDA)、水、芳香胺和芳香醛的四组分反应合成紫杉醇C-13侧链前体的方法.从经济性和实用性出发, 筛选了一系列金属催化剂, 最终确定使用廉价、催化活性又相对较好的Cu(OTf)2替代Rh2(OAc)4.在后续多组分产物到噁唑烷型侧链的合成中, 将原先所需的6到7步反应缩减为4步, 简化了后处理步骤, 最终以10%左右的总收率得到了共14种顺式噁唑烷型紫杉醇侧链.该路线中每一步反应均可放大至10 g, 且操作步骤不需要改变, 得到的结果也与小试时几乎一致, 拥有一定的应用价值.随后利用所得侧链, 合成了14种紫杉醇衍生物, 并在进一步的抗肿瘤细胞活性测试中发现了多个活性优异的新型化合物.

    表 3

    表 3  紫杉醇衍生物的抗肿瘤细胞活性a
    Table 3.  Anti-tumor activity of the paclitaxel analogues
    下载: 导出CSV
    Entry Mr IC50/(μmol·L－1)
    H460 MG63 KB PC9
    Paclitaxel 853.33 0.0119 0.0115 0.0006 0.0031
    anti-14b 888.36 ＞50 ＞50 9.6593 30.6455
    14e 883.34 0.0203 0.0218 0.0004 0.0064
    14h 896.37 0.0152 0.0455 0.0022 0.0145
    14i 913.35 0.1551 0.2918 0.0594 0.0930
    14j 843.31 0.0046 0.0059 0.0005 0.0046
    14k 859.29 0.0037 0.0014 ＜0.0005 0.0010
    14m 957.29 13.7922 20.3900 6.0461 13.7886
    Cyclo-14m 1075.33 ＞50 ＞50 ＞50 ＞50
    Cyclo-14n 1021.36 ＞50 ＞50 30.4081 ＞50
    Cabazitaxel 835.38 ＜0.0005 0.0080 ＜0.0005 ＜0.0005
    15a 839.35 0.0179 0.0029 ＜0.0005 0.0012
    15h 882.39 0.0018 0.0046 ＜0.0005 0.0017
    a The data provided by collaborators from School of Pharmaceutical Sciences, Sun Yat-sen University.

    值得注意的是, 我们成功地将多组分方法学的研究成果应用到了紫杉醇类似物的合成中, 大大提高了侧链的多样性和合成效率, 为后续的构效关系研究提供了相当大的便利.这也是多组分反应方法学应用价值的体现.

    3.   实验部分

    3.1   仪器与试剂

    核磁共振氢谱和碳谱由Bruker Avance Ⅲ-400核磁共振仪测定; 高分辨质谱由HRMS (ESI) Waters Synapt质谱仪测定; 高效液相色谱(HPLC)由Thermol Scientific Dionex Ultimate 3000型高效液相色谱仪测定.

    实验所用溶剂均采购于上海润捷化学试剂有限公司, 其中四氢呋喃使用前经无水处理.

    3.2   实验方法

    以紫杉醇(14a)、7, 10-二甲氧基紫杉醇(15a)以及噁唑烷型紫杉醇侧链(4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸(9a)及其前体(5a, 6a, 7a, 8a)为例, 其余衍生物的合成方法均与示例相同.

    3.2.1   N-对甲氧基苯基-(2R, 3S)-苯基异丝氨酸乙酯(syn-5a)的合成

    将化合物3(50 mmol), 4a (52.5 mmol), H2O (2 mL), Cu(OTf)2 (2.5 mmol)加入500 mL烧瓶中, 加入100 mL二氯甲烷(DCM)溶解, 搅拌30 min.之后将化合物2 (75 mmol)溶于30 mL DCM后, 用恒压滴液漏斗缓慢滴入(30 mL/h).继续常温搅拌0.5 h后, 反应完毕, 加入25 mL水分液, 取DCM相, 干燥浓缩.最后以V(石油醚):V(乙酸乙酯)＝10:1为洗脱剂, 柱层析分离出4.11 g白色固体syn-5a, 总产率58%, 顺式产物收率26%[9].

    化合物syn-5b~5o的合成步骤与上述相同, 所得粗产物经快速柱层析纯化后直接进入下一步合成.

    3.2.2   (2R, 3S)-苯基异丝氨酸乙酯(6a)的合成

    将化合物syn-5a (25 mmol)加入500 mL烧瓶中, 加入60 mL乙腈和45 mL水将底物溶解.再将TCCA (13.75 mmol)加入烧瓶, 反应液变为紫黑色, 随后加入1 mol/L H2SO4 25 mL, 室温下搅拌过夜.反应液将慢慢地由紫黑色浊液变为橙红色溶液, 最后在反应进行约12~16 h时, 反应液变为黄色溶液. LC-MS监测反应, 反应结束后加入DCM (30 mL×3)清洗反应液, 分液后取水相.向水相中加入2 mol/L NaOH溶液调节pH值至9~10, 随后加入乙酸乙酯萃(25 mL×2), 收集乙酸乙酯相, 干燥浓缩后得到白色略带棕色固体.将所得固体在V(石油醚):V(乙酸乙酯)＝20:1条件下进行重结晶, 可以得到3.15 g白色固体syn-6a, 收率60%[9].

    化合物syn-6b~6o的合成步骤与上述相同, 所得白色略带棕色固体粗产物不经重结晶直接进入下一步合成.

    3.2.3   N-苯甲酰基-(2R, 3S)-苯基异丝氨酸乙酯(7a)的合成

    将化合物6a (15 mmol)加入250 mL烧瓶中, 加入60 mL乙酸乙酯和30 mL饱和碳酸氢钠溶液溶解.在冰水浴下缓慢加入苯甲酰氯(16.5 mmol), 10 min滴加完毕, 随后自然升温至室温, 继续反应2 h.薄层色谱(TLC)和LC-MS监测反应, 反应结束后分液, 取乙酸乙酯相, 干燥浓缩, 得到白色固体.将所得固体在V(石油醚):V(乙酸乙酯)＝10:1条件下进行重结晶, 可以得到3.85 g白色固体syn-7a, 收率82%[13]. 1H NMR (400 MHz, CDCl3) δ: 7.77 (d, J＝7.2 Hz, 2H), 7.51 (t, J＝7.7 Hz, 1H), 7.48~7.40 (m, 4H), 7.37 (t, J＝7.1 Hz, 2H), 7.31 (d, J＝7.6 Hz, 1H), 7.00 (d, J＝9.0 Hz, 1H), 5.76 (dd, J＝9.1, 1.3 Hz, 1H), 4.62 (s, 1H), 4.36~4.23 (m, 2H), 3.31 (s, 1H), 1.30 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 173.0, 166.8, 138.7, 134.2, 131.8, 128.7, 128.7, 127.9, 127.1, 126.9, 73.3, 62.8, 54.7, 14.1. HRMS (ESI) calcd for C18H19NNaO4 [M+Na]+: 336.1212, found 336.1225.

    化合物7b~7o的合成步骤与7a相同.

    N-苯甲酰基-(2R, 3S)-3-(4-氯苯基)异丝氨酸乙酯(7b):白色固体3.97g, 收率80%. 1H NMR (400 MHz, CDCl3) δ: 7.73 (d, J＝7.3 Hz, 2H), 7.48 (t, J＝7.4 Hz, 1H), 7.43~7.32 (m, 4H), 7.28 (d, J＝8.5 Hz, 2H), 7.18 (d, J＝9.0 Hz, 1H), 5.69 (dd, J＝9.0, 1.5 Hz, 1H), 4.54 (dd, J＝3.8, 2.2 Hz, 1H), 4.31~4.18 (m, 2H), 3.75 (d, J＝4.0 Hz, 1H), 1.26 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.6, 167.0, 137.4, 133.9, 133.7, 131.9, 128.8, 128.7, 128.4, 127.1, 73.2, 62.7, 54.4, 14.1. HRMS (ESI) calcd for C18H19NO4Cl [M+H]+: 348.1003, found 348.1012.

    N-苯甲酰基-(2R, 3S)-3-(4-甲基苯基)异丝氨酸乙酯(7c):白色固体4.10 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J＝7.7 Hz, 2H), 7.51 (t, J＝7.0 Hz, 1H), 7.43 (t, J＝7.5 Hz, 2H), 7.34 (d, J＝7.6 Hz, 2H), 7.17 (d, J＝7.7 Hz, 2H), 6.98 (d, J＝6.3 Hz, 1H), 5.72 (d, J＝9.0 Hz, 1H), 4.60 (s, 1H), 4.35~4.23 (m, 2H), 3.34~3.30 (m, 1H), 2.33 (s, 3H), 1.30 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 173.0, 166.8, 137.6, 135.7, 134.2, 131.7, 129.4, 128.7, 127.1, 126.8, 73.4, 62.7, 54.6, 21.1, 14.1. HRMS (ESI) calcd for C19H21NO4Na [M+Na]+: 350.1368, found 350.1382.

    N-苯甲酰基-(2R, 3S)-3-(4-甲氧基苯基)异丝氨酸乙酯(7d):白色固体4.18 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, J＝7.2 Hz, 2H), 7.57~7.23 (m, 5H), 7.01 (t, J＝9.3 Hz, 1H), 6.88 (d, J＝8.7 Hz, 2H), 5.69 (t, J＝10.9 Hz, 1H), 4.58 (s, 1H), 4.36~4.20 (m, 2H), 3.78 (s, 3H), 3.46 (s, 1H), 1.29 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 173.0, 172.7, 166.8, 159.2, 154.6, 134.2, 134.0, 132.1, 131.8, 131.7, 130.9, 128.9, 128.7, 128.6, 128.2, 127.1, 127.0, 126.6, 122.7, 73.4, 73.2, 62.8, 62.7, 56.2, 55.3, 54.3, 53.9, 14.1. HRMS (ESI) calcd for C19H21NO5Na [M+Na]+: 366.1317, found 366.1320.

    N-(4-甲氧基苯甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7e):白色固体4.05 g, 收率80%. 1H NMR (400 MHz, CDCl3) δ: 7.74 (d, J＝8.7 Hz, 2H), 7.45 (d, J＝7.4 Hz, 2H), 7.36 (t, J＝7.4 Hz, 2H), 7.29 (t, J＝7.3 Hz, 1H), 6.92 (d, J＝8.7 Hz, 2H), 6.91 (s, 1H), 5.74 (d, J＝8.0 Hz, 1H), 4.62 (dd, J＝3.5, 2.2 Hz, 1H), 4.34~4.22 (m, 2H), 3.84 (s, 3H), 3.34 (d, J＝3.8 Hz, 1H), 1.29 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 173.0, 166.3, 162.4, 138.9, 128.9, 128.7, 127.9, 126.9, 126.4, 113.8, 73.4, 62.7, 55.5, 54.7, 14.1. HRMS (ESI) calcd for C19H21NO5Na [M+ Na]+: 366.1317, found 366.1321.

    N-(4-氯苯甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7f):白色固体3.85 g, 收率79%. 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, J＝8.5 Hz, 2H), 7.51~7.33 (m, 6H), 7.30 (t, J＝7.2 Hz, 1H), 6.95 (d, J＝8.9 Hz, 1H), 5.73 (d, J＝8.2 Hz, 1H), 4.61 (s, 1H), 4.35~4.23 (m, 2H), 3.27 (d, J＝3.5 Hz, 1H), 1.30 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.9, 165.7, 138.6, 138.0, 132.5, 128.9, 128.8, 128.5, 128.0, 126.9, 73.2, 62.8, 54.8, 14.1. HRMS (ESI) calcd for C18H19NO4Cl [M+H]+: 348.1003, found 348.1012.

    N-(4-三氟甲基苯甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7g):白色固体4.21 g, 收率84%. 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J＝8.1 Hz, 2H), 7.68 (d, J＝8.1 Hz, 2H), 7.45 (d, J＝7.4 Hz, 2H), 7.37 (t, J＝7.3 Hz, 2H), 7.31 (t, J＝7.3 Hz, 1H), 7.10 (d, J＝9.0 Hz, 1H), 5.76 (dd, J＝9.2, 1.4 Hz, 1H), 4.62 (d, J＝1.9 Hz, 1H), 4.35~4.23 (m, 2H), 3.40 (s, 1H), 1.30 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.9, 165.6, 138.4, 137.4, 133.5 (q, J＝33.4 Hz), 128.8, 128.1, 127.6, 126.9, 125.7 (q, J＝3.6 Hz), 123.6 (q, J＝271.3 Hz), 73.2, 62.8, 54.9, 14.1. HRMS (ESI) calcd for C19H18F3NO4Na [M+Na]+: 404.1124, found 404.1129.

    N-(4-二甲氨基苯甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7h):白色固体4.30 g, 收率85%. 1H NMR (400 MHz, CDCl3) δ: 7.61 (d, J＝8.8 Hz, 2H), 7.37 (d, J＝7.5 Hz, 2H), 7.27 (t, J＝7.4 Hz, 2H), 7.19 (t, J＝7.3 Hz, 1H), 6.78 (d, J＝9.0 Hz, 1H), 6.59 (d, J＝8.8 Hz, 2H), 5.67 (d, J＝9.0 Hz, 1H), 4.54 (d, J＝2.1 Hz, 1H), 4.26~4.14 (m, 2H), 2.94 (s, 6H), 1.21 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.0, 165.7 151.67, 138.2 127.6, 127.6 126.7 125.9 119.7, 110.1 72.5, 61.6, 53.7 39.1, 13.1. HRMS (ESI) calcd for C20H24N2O4Na [M+Na]+: 379.1634, found 379.1640.

    N-[4-(3, 5-二甲氧基苯甲酰基)]-(2R, 3S)-3-苯基异丝氨酸乙酯(7i):白色固体3.98 g, 收率78%. 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, J＝7.4 Hz, 2H), 7.36 (t, J＝7.4 Hz, 2H), 7.30 (t, J＝7.2 Hz, 1H), 6.97 (d, J＝9.1 Hz, 1H), 6.89 (d, J＝2.2 Hz, 2H), 6.58 (t, J＝2.1 Hz, 1H), 5.72 (dd, J＝9.1, 1.4 Hz, 1H), 4.61 (d, J＝2.0 Hz, 1H), 4.36~4.23 (m, 2H), 3.81 (s, 6H), 1.31 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.9 166.7 160.97, 138.7 136.4 128.7, 127.9, 126.9, 105.1 103.6, 73.3 62.8 55.6 54.8, 14.1. HRMS (ESI) calcd for C20H23NO6Na [M+Na]+: 396.1424, found 396.1420.

    N-(2-呋喃甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7j):白色固体4.00 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.49~7.42 (m, 3H), 7.36 (t, J＝7.4 Hz, 2H), 7.30 (t, J＝7.2 Hz, 1H), 7.20 (d, J＝9.3 Hz, 1H), 7.10 (d, J＝3.4 Hz, 1H), 6.49 (dd, J＝3.3, 1.6 Hz, 1H), 5.71 (d, J＝9.4 Hz, 1H), 4.59 (s, 1H), 4.29 (qd, J＝7.1, 1.2 Hz, 2H), 3.35 (s, 1H), 1.31 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.8 157.6 147.5 144.2 138.64, 128.7, 128.0, 127.0, 114.8, 112.2, 73.2, 62.8, 54.0, 14.1. HRMS (ESI) calcd for C16H18NO5 [M+H]+: 304.1137, found 304.1134.

    N-(2-噻吩甲酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7k):白色固体4.10 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.52 (d, J＝3.4 Hz, 1H), 7.49~7.42 (m, 3H), 7.36 (t, J＝7.4 Hz, 2H), 7.29 (t, J＝7.2 Hz, 1H), 7.06 (t, J＝4.9 Hz, 1H), 6.90 (d, J＝9.0 Hz, 1H), 5.71 (d, J＝9.1 Hz, 1H), 4.60 (s, 1H), 4.34~4.22 (m, 2H), 3.42 (d, J＝3.1 Hz, 1H), 1.29 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 172.8, 161.2, 138.6, 138.3, 130.4, 128.7, 128.5, 127.9, 127.7, 126.9, 73.2, 62.8, 54.7, 14.1. HRMS (ESI) calcd for C16H18NO4S [M+H]+: 320.0982, found 320.0988.

    N-环丙甲酰基-(2R, 3S)-3-苯基异丝氨酸乙酯(7l):白色固体3.80 g, 收率78%. 1H NMR (400 MHz, CDCl3) δ: 7.32 (d, J＝7.7 Hz, 2H), 7.27 (t, J＝7.1 Hz, 2H), 7.21 (t, J＝7.1 Hz, 1H), 6.47 (d, J＝9.0 Hz, 1H), 5.49 (d, J＝9.2 Hz, 1H), 4.43 (s, 1H), 4.25~4.13 (m, 2H), 3.34 (d, J＝3.5 Hz, 1H), 1.34~1.28 (m, 1H), 1.21 (t, J＝7.1 Hz, 3H), 0.88~0.82 (m, 2H), 0.69~0.61 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 172.0, 171.9, 138.0, 127.6, 126.7, 125.9, 72.4, 61.5, 53.5, 13.6, 13.1, 6.4, 6.4. HRMS (ESI) calcd for C15H20NO4 [M+H]+: 278.1392, found 278.1364.

    N-(4-三氟甲基苯磺酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7m):白色固体4.16 g, 收率81%. 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J＝8.2 Hz, 2H), 7.39 (d, J＝8.3 Hz, 2H), 7.12~6.93 (m, 5H), 5.88 (d, J＝9.8 Hz, 1H), 4.84 (dd, J＝9.8, 2.1 Hz, 1H), 4.27 (s, 1H), 4.20 (q, J＝7.1 Hz, 2H), 3.36 (s, 1H), 1.26 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.0, 142.9, 135.4, 132.9 (q, J＝33.5 Hz), 127.4, 127.1, 126.4, 126.0, 124.7 (q, J＝3.6 Hz), 122.1 (q, J＝273.0 Hz), 73.6, 62.0, 58.5, 13.1. HRMS (ESI) calcd for C18H18F3NO5SNa [M+Na]+: 440.0755, found 440.0793.

    N-(4-甲基苯磺酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7n):白色固体4.05 g, 收率81%. 1H NMR (400 MHz, CDCl3) δ: 7.43 (d, J＝8.2 Hz, 2H), 7.13~7.02 (m, 5H), 6.99 (d, J＝8.0 Hz, 2H), 5.50 (d, J＝9.7 Hz, 1H), 4.79 (dd, J＝9.7, 2.2 Hz, 1H), 4.24 (s, 1H), 4.19~4.08 (m, 2H), 3.19 (s, 1H), 2.25 (s, 3H), 1.23 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.0, 142.1, 136.6, 136.3, 128.2, 127.3, 126.7, 126.0, 125.9, 73.2, 61.8, 58.1, 20.4, 13.0. HRMS (ESI) calcd for C18H22NO5S [M+H]+: 364.1219, found 364.1220.

    N-(4-乙酰胺基苯磺酰基)-(2R, 3S)-3-苯基异丝氨酸乙酯(7o):白色固体4.25 g, 收率82%. 1H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H), 8.13 (d, J＝9.7 Hz, 1H), 7.54~7.36 (m, 4H), 7.21~7.03 (m, 5H), 5.55 (d, J＝6.5 Hz, 1H), 4.66 (dd, J＝9.6, 4.2 Hz, 1H), 4.16 (t, J＝5.1 Hz, 1H), 4.01~3.87 (m, 2H), 2.04 (s, 3H), 1.08 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ: 171.3, 168.7, 142.1, 138.2, 135.3, 127.5, 127.4, 127.3, 126.9, 117.9, 74.4, 60.3, 60.2, 24.1, 13.9. HRMS (ESI) calcd for C19H22N2O6SNa [M+Na]+: 429.1096, found 429.1084.

    3.2.4   (4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-苯基- 5-噁唑啉羧酸乙酯(8a)的合成

    将化合物7a (12 mmol)和对甲苯磺酸吡啶盐(PPTS, 1.2 mmol)加入250 mL烧瓶中, 加入100 mL甲苯, 升温至100 ℃, 搅拌10 min至底物溶解.之后向烧瓶中滴加对甲氧基苯甲醛二甲缩醛(18 mmol), 保持100 ℃反应3 h. TLC监测反应, 反应结束后降低至室温, 直接进行柱层析.以V(石油醚):V(乙酸乙酯)＝8:1为洗脱剂, 可以分离得到4.41 g黄色油状液体8a, 收率85%. 1H NMR (400 MHz, CDCl3) δ: 7.74~7.36 (m, 2H), 7.36~7.28 (m, 4H), 7.35~7.12 (m, 6H), 6.71~6.99 (m, 3H), 5.35 (s, 1H), 4.85 (s, 1H), 4.28 (q, J＝7.0 Hz, 2H), 3.81 (s, 3H), 1.30 (t, J＝7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 170.8, 169.9, 160.0, 139.0, 136.8, 134.0, 129.7, 128.8, 128.6, 128.5, 128.2, 127.0, 113.6, 91.3, 82.4, 64.9, 62.0, 55.3, 14.2. HRMS (ESI) calcd for C26H26NO5 [M+H]+: 432.1844, found 432.1841.

    (4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-(4-氯苯基)-5-噁唑啉羧酸乙酯(8b):黄色油状液体4.54 g, 收率84%. 1H NMR (400 MHz, CDCl3) δ: 7.44~7.34 (m, 2H), 7.33~7.10 (m, 9H), 6.94~6.76 (m, 3H), 5.38 (s, 1H), 4.79 (s, 1H), 4.29 (q, J＝7.1 Hz, 2H), 3.81 (s, 3H), 1.31 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.8, 169.8, 160.0, 137.8, 135.6, 134.0, 130.7, 129.8, 128.8, 128.6, 128.3, 126.9, 113.6, 91.3, 82.0, 64.2, 62.1, 55.3, 14.2. HRMS (ESI) calcd for C26H25NO5Cl [M+H]+: 466.1362, found 466.1369.

    (4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-(4-甲基苯基)-5-噁唑啉羧酸乙酯(8c):黄色油状液体4.25 g, 收率82%. 1H NMR (400 MHz, CDCl3) δ: 7.58~7.36 (m, 2H), 7.35 (t, J＝7.5 Hz, 1H), 7.29 (d, J＝7.5 Hz, 2H), 7.22 (t, J＝7.1 Hz, 2H), 7.17~6.99 (m, 4H), 6.96~6.70 (m, 3H), 5.34 (s, 1H), 4.82 (s, 1H), 4.28 (q, J＝7.0 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 1.30 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.9, 170.2, 159.9, 137.8, 136.3, 135.8, 130.6, 130.1, 129.3, 128.8, 128.2, 127.0, 113.5, 91.2, 64.8, 61.9, 55.3, 21.1, 14.2. HRMS (ESI) calcd for C27H28NO5 [M+H]+: 446.1967, found 446.1980.

    (4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-(4-甲氧基苯基)-5-噁唑啉羧酸乙酯(8d):黄色油状液体4.46 g, 收率84%. 1H NMR (400 MHz, CDCl3) δ: 7.61~7.31 (m, 3H), 7.32~7.15 (m, 6H), 7.14 (br. s, 1H), 6.93~6.73 (m, 4H), 5.33 (s, 1H), 4.79 (d, J＝12.2 Hz, 1H), 4.29 (qd, J＝7.1, 2.0 Hz, 2H), 3.99~3.74 (m, 6H), 1.30 (t, J＝6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 170.1, 169.8, 160.0, 159.3, 154.7, 135.7, 128.7, 128.6, 128.3, 128.2, 127.0, 122.6, 113.9, 113.6, 111.9, 91.2, 82.0, 64.1, 62.0, 56.2, 55.3, 14.2. HRMS (ESI) calcd for C27H28NO6 [M+H]+: 462.1892, found 462.1885.

    (4S, 5R)-3-(4-甲氧基苯甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8e):黄色油状液体4.60 g, 收率85%. 1H NMR (400 MHz, CDCl3) δ: 7.47 (d, J＝7.1 Hz, 2H), 7.36~7.23 (m, 7H), 6.96 (s, 1H), 6.86 (d, J＝8.6 Hz, 2H), 6.72 (d, J＝8.7 Hz, 2H), 5.45 (s, 1H), 4.83 (d, J＝1.4 Hz, 1H), 4.26 (q, J＝7.1 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 1.29 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.8, 170.1, 161.6, 159.9, 139.6, 130.3, 129.3, 128.7, 128.7, 128.0, 127.8, 127.0, 113.5, 113.5, 91.2, 82.3, 65.3, 61.9, 55.3, 55.3, 14.2. HRMS (ESI) calcd for C27H28NO6 [M+H]+: 462.1892, found 462.1887.

    (4S, 5R)-3-(4-氯苯甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8f):黄色油状液体4.10 g, 收率80%. 1H NMR (400 MHz, CDCl3) δ: 7.43~7.34 (m, 2H), 7.34~7.09 (m, 9H), 6.95~6.67 (m, 3H), 5.38 (s, 1H), 4.79 (s, 1H), 4.29 (q, J＝7.1 Hz, 2H), 3.81 (s, 3H), 1.31 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.8, 169.8, 160.0, 137.8, 135.6, 1334.0, 130.7, 129.8, 128.8, 128.6, 128.3, 126.9, 113.6, 91.3, 82.0, 64.2, 62.1, 55.29, 55.3, 14.2. HRMS (ESI) calcd for C26H25NO5Cl [M+H]+: 466.1362, found 466.1375.

    (4S, 5R)-3-(4-三氟甲基苯甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8g):黄色油状液体4.19 g, 收率80%. 1H NMR (400 MHz, CDCl3) δ: 7.49 (d, J＝8.1 Hz, 2H), 7.47~7.04 (m, 9H), 6.84 (s, 3H), 5.30 (br. s, 1H), 4.88 (s, 1H), 4.30 (q, J＝7.0 Hz, 2H), 3.81 (s, 3H), 1.32 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 169.9, 160.1, 139.1, 138.8, 132.2 (q, J＝34.1 Hz), 129.4, 128.8, 128.3, 127.3, 127.1, 126.0 (q, J＝272.8 Hz), 125.3 (q, J＝3.7 Hz), 113.6, 91.3, 81.9, 65.0, 62.1, 55.3, 14.2. HRMS (ESI) calcd for C27H25F3NO5 [M+H]+: 500.1636, found 500.1647.

    (4S, 5R)-3-(4-二甲氨基苯甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8h):无色油状液体4.67 g, 收率85%. 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, J＝8.5 Hz, 2H), 7.30~7.17 (m, 7H), 6.96 (s, 1H), 6.79 (d, J＝8.7 Hz, 2H), 6.39 (d, J＝8.9 Hz, 2H), 5.46 (s, 1H), 4.73 (d, J＝1.7 Hz, 1H), 4.24~4.12 (m, 2H), 3.74 (s, 3H), 2.86 (s, 6H), 1.21 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.4, 169.2, 158.7, 151.1, 139.0, 129.7, 128.5, 127.7, 127.6, 126.7, 126.0, 120.9, 112.4, 109.7, 90.2, 81.4, 64.5, 60.8, 54.3, 39.0, 13.1. HRMS (ESI) calcd for C28H31N2O5 [M+H]+: 475.2256, found 475.2264.

    (4S, 5R)-3-(3, 5-二甲氧基苯甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8i):无色油状液体4.24 g, 收率80%. 1H NMR (400 MHz, CDCl3) δ: 7.69~7.39 (m, 2H), 7.37~7.16 (m, 5H), 7.05~6.71 (m, 3H), 6.43 (s, 3H), 5.35 (s, 1H), 4.84 (s, 1H), 4.29 (q, J＝7.1 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 6H), 1.32 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 171.8, 170.0, 160.4, 159.9, 137.3, 130.1, 128.8, 128.7, 128.0, 127.0, 113.5, 104.6, 104.1, 91.1, 62.0, 55.3, 55.1, 29.7, 14.2. HRMS (ESI) calcd for C28H30NO7 [M+H]+: 492.2022, found 492.2040.

    (4S, 5R)-3-(2-呋喃甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8j):无色油状液体4.28 g, 收率82%. 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J＝8.4 Hz, 2H), 7.38~7.27 (m, 6H), 7.02 (s, 1H), 6.93 (d, J＝3.2 Hz, 1H), 6.86 (d, J＝8.8 Hz, 2H), 6.36 (dd, J＝3.5, 1.7 Hz, 1H), 5.81 (d, J＝2.7 Hz, 1H), 4.91 (d, J＝2.3 Hz, 1H), 4.30 (q, J＝7.1 Hz, 2H), 3.80 (s, 3H), 1.31 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 170.0, 159.9, 159.0, 147.0, 145.0, 139.1, 129.8, 129.0, 128.6, 127.9, 127.0, 117.5, 113.5, 111.7, 91.5, 64.1, 62.0, 55.3, 14.2. HRMS (ESI) calcd for C24H24NO6 [M+H]+: 422.1574, found 422.1570.

    (4S, 5R)-3-(2-噻吩甲酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8k):无色油状液体4.33 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.53 (d, J＝8.6 Hz, 2H), 7.42 (d, J＝5.0 Hz, 1H), 7.38~7.30 (m, 5H), 7.03 (d, J＝3.7 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J＝8.6 Hz, 2H), 6.84 (t, J＝4.3 Hz, 1H), 5.73 (d, J＝2.1 Hz, 1H), 4.92 (d, J＝2.2 Hz, 1H), 4.29 (q, J＝7.5 Hz, 2H), 3.81 (s, 3H), 1.29 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 170.0, 164.0, 160.1, 139.0, 138.4, 131.1, 129.8, 129.7, 129.1, 128.8, 128.2, 127.5, 127.0, 113.5, 91.7, 82.7, 65.1, 62.0, 55.3, 14.2. HRMS (ESI) calcd for C24H24NO5S [M+H]+: 438.1365, found 438.1369.

    (4S, 5R)-3-环丙甲酰基-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8l):黄色油状液体3.89 g, 收率75%. 1H NMR (400 MHz, CDCl3) δ: 7.47~7.20 (m, 7H), 6.81 (d, J＝8.6 Hz, 2H), 6.65 (s, 1H), 5.48 (s, 1H), 4.78 (d, J＝2.6 Hz, 1H), 4.33~4.14 (m, 2H), 3.74 (s, 3H), 1.26 (t, J＝6.9 Hz, 3H), 0.99~0.89 (m, 1H), 0.89~0.75 (m, 2H), 0.69~0.42 (m, 2H); 13C NMR (101 MHz, CDCl3) δ: 171.9, 169.1, 138.3, 129.1, 127.8, 127.1, 112.8, 99.0, 90.3, 62.6, 61.1, 60.8, 54.3, 13.2, 12.4, 7.3. HRMS (ESI) calcd for C23H26NO5 [M+H]+: 396.1747, found 396.1743.

    (4S, 5R)-3-(4-三氟甲基苯磺酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8m):无色油状液体4.08 g, 收率78%. 1H NMR (400 MHz, CDCl3) δ: 7.55~7.43 (m, 4H), 7.33 (d, J＝8.6 Hz, 2H), 7.30~7.21 (m, 5H), 6.76 (d, J＝8.7 Hz, 2H), 6.37 (s, 1H), 5.17 (d, J＝3.9 Hz, 1H), 4.66 (d, J＝3.9 Hz, 1H), 4.06 (q, J＝7.1 Hz, 2H), 3.73 (s, 3H), 1.19 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 167.9, 159.6, 140.8, 137.5, 133.5 (q, J＝33.4 Hz), 128.2, 127.8, 127.5, 127.2, 127.0, 126.2, 124.8 (q, J＝3.9 Hz), 119.4 (q, J＝273.1 Hz), 112.8, 92.1, 81.3, 64.2, 61.0, 54.3, 13.0. HRMS (ESI) calcd for C26H25F3NO6S [M+H]+: 536.1366, found 536.1377.

    (4S, 5R)-3-(4-甲基苯磺酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8n):无色油状液体4.27 g, 收率83%. 1H NMR (400 MHz, CDCl3) δ: 7.53 (d, J＝8.2 Hz, 2H), 7.41 (d, J＝8.6 Hz, 2H), 7.30~7.13 (m, 7H), 6.81 (d, J＝8.7 Hz, 2H), 6.36 (s, 1H), 5.04 (d, J＝4.5 Hz, 1H), 4.57 (d, J＝4.5 Hz, 1H), 4.03~3.92 (m, 2H), 3.74 (s, 3H), 2.34 (s, 3H), 1.14 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 167.9, 159.3, 143.1, 137.8, 133.5, 128.6, 128.3, 127.8, 127.6, 127.1, 126.1, 112.7, 92.1, 81.3, 64.5, 60.8, 54.3, 20.5, 13.0. HRMS (ESI) calcd for C26H28NO6S [M+H]+: 482.1638, found 482.1645.

    (4S, 5R)-3-(4-乙酰胺基苯磺酰基)-2-(4-甲氧基苯基)-4-苯基-5-噁唑啉羧酸乙酯(8o):无色油状液体3.82 g, 收率73%. 1H NMR (400 MHz, CDCl3) δ: 7.83 (s, 1H), 7.67~7.55 (m, 4H), 7.47 (d, J＝8.6 Hz, 2H), 7.39~7.26 (m, 5H), 6.87 (d, J＝8.6 Hz, 2H), 6.40 (s, 1H), 5.11 (d, J＝4.4 Hz, 1H), 4.66 (d, J＝4.4 Hz, 1H), 4.13~4.01 (m, 2H), 3.80 (s, 3H), 2.12 (s, 3H), 1.21 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 168.9, 168.9, 160.4, 142.8, 138.7, 131.6, 129.2, 129.1, 128.9, 128.7, 128.3, 127.1, 119.1, 113.8, 93.2, 82.3, 65.6, 62.0, 55.3, 24.6, 14.0. HRMS (ESI) calcd for C27H29N2O7S [M+H]+: 525.1695, found 525.1680.

    3.2.5   (4S, 5R)-3-苯甲酰基-2-(4-甲氧基苯基)-4-苯基- 5-噁唑啉羧酸(9a)的合成

    向化合物8a (11 mmol)加入40 mL甲醇和20 mL水, 再加入NaOH (33 mmol), 室温搅拌2 h. TLC监测反应, 反应结束后真空旋干溶剂, 再向得到的残余物中加入25 mL水溶解.随后向溶液中加入1 mol/L HCl调节pH值至3~4, 有大量白色固体析出, 过滤、干燥得到4.21 g黄色固体9a, 收率95%[13]. 1H NMR (400 MHz, DMSO-d6) δ: 13.64 (s, 1H), 7.55~7.35 (m, 2H), 7.35~7.12 (m, 10H), 6.90 (d, J＝7.9 Hz, 2H), 6.63 (s, 1H), 5.30 (s, 1H), 4.90 (s, 1H), 3.76 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ: 170.9, 159.4, 138.4, 135.7, 132.4, 130.5, 129.6, 128.7, 128.4, 128.4, 126.3, 113.5, 90.0, 55.1. HRMS (ESI) calcd for C24H21NO5Na [M+Na]+: 426.1317, found 426.1310.

    3.2.6   紫杉醇(14a)的合成

    将化合物10 (0.1 mmol)、化合物9a (0.23 mmol)、二甲氨基吡啶(DMAP, 0.23 mmol)和2.5 mL无水甲苯加入50 mL烧瓶中, 加热至70 ℃使反应液溶清, 随后加入DCC (0.33 mmol), 搅拌1 h. TCL和LC-MS监测反应, 反应结束后过滤, 收集滤液.最后以V(石油醚):V(乙酸乙酯)＝2:1为洗脱剂柱层析分离得到白色固体12a, 收率为95%.向所得化合物12a (0.1 mmol)中加入3 mL无水乙醇, 呈白色浊液, 再向反应液中加入20%~30%的HCl/EtOH溶液0.5 mL, 室温下搅拌24 h, 反应液澄清. LC-MS监测反应, 反应结束后加入1.5 mL饱和NaHCO3溶液、0.5 mL水和10 mL乙酸乙酯萃取分液, 水相再用10 mL乙酸乙酯反萃, 合并乙酸乙酯相, 干燥浓缩.最后以V(二氯甲烷):V(甲醇)＝20:1为洗脱剂柱层析分离得到46 mg白色固体14a, 收率为57%.

    3'-(4-氯苯基)紫杉醇(14b):白色固体26 mg, 产率48%. m.p. 159~160 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J＝7.5 Hz, 2H), 7.66 (d, J＝7.4 Hz, 2H), 7.54 (t, J＝7.4 Hz, 1H), 7.49~7.29 (m, 9H), 6.97 (d, J＝8.8 Hz, 1H), 6.25 (s, 1H), 6.13 (t, J＝8.6 Hz, 1H), 5.67 (d, J＝8.8 Hz, 1H), 5.59 (d, J＝7.0 Hz, 1H), 4.90 (d, J＝8.7 Hz, 1H), 4.56 (s, 1H), 4.39 (dd, J＝10.3, 8.52 Hz, 1H), 4.22 (d, J＝8.4 Hz, 1H), 4.09 (d, J＝8.6 Hz, 1H), 3.79 (d, J＝7.0 Hz, 1H), 3.75~3.59 (m, 1H), 2.60~2.44 (m, 2H), 2.31 (dd, J＝15.1, 9.2 Hz, 1H), 2.13 (s, 3H), 2.14 (s, 3H), 2.11~2.08 (m, 1H), 1.97 (s, 3H), 1.86~1.80 (m, 1H), 1.61 (s, 3H), 1.14 (s, 3H), 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.6, 171.4, 170.1, 168.5, 166.0, 141.0, 136.4, 133.3, 132.8, 132.6, 132.0, 131.1, 129.0, 128.2, 128.1, 127.8, 127.7, 127.7, 126.1, 83.4, 80.2, 78.2, 76.2, 75.4, 74.5, 73.8, 72.2, 71.6, 71.2, 57.6, 53.6, 44.8, 42.1, 35.0, 34.6, 28.7, 25.74, 21.6, 20.5, 19.8, 14.3, 8.5. HRMS (ESI) calcd for C47H51ClNO14 [M+H]+: 888.2998, found 888.2982.

    3'-(N-对甲氧基苯甲酰基)紫杉醇(14e):白色固体27 mg, 产率51%. m.p. 158~159 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.05 (d, J＝7.6 Hz, 2H), 7.63 (d, J＝8.6 Hz, 2H), 7.54 (t, J＝7.3 Hz, 1H), 7.46~7.36 (m, 4H), 7.33 (t, J＝7.4 Hz, 2H), 7.26 (t, J＝7.1 Hz, 1H), 6.90 (d, J＝8.7 Hz, 1H), 6.79 (d, J＝8.6 Hz, 2H), 6.19 (s, 1H), 6.13 (t, J＝8.7 Hz, 1H), 5.68 (d, J＝8.5 Hz, 1H), 5.59 (d, J＝7.0 Hz, 1H), 4.86 (d, J＝9.2 Hz, 1H), 4.69 (s, 1H), 4.31 (t, J＝7.5 Hz, 1H), 4.21 (d, J＝8.4 Hz, 1H), 4.11 (d, J＝8.4 Hz, 1H), 3.74 (s, 3H), 3.73~3.68 (m, 1H), 2.51~2.39 (m, 2H), 2.30 (s, 3H), 2.27~2.17 (m, 2H), 2.15 (s, 3H), 1.84~1.79 (m, 1H), 1.71 (s, 3H), 1.60 (s, 3H), 1.15 (s, 3H), 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.6, 171.7, 170.2, 169.4, 166.0, 165.7, 161.5, 141.0, 137.1, 132.7, 132.1, 129.2, 128.2, 128.0, 127.9, 127.7, 127.3, 126.0, 124.8, 112.8, 83.4, 80.1, 78.0, 76.2, 75.5, 74.6, 73.9, 72.4, 71.2, 71.2, 57.6, 54.4, 54.1, 44.6, 42.1, 34.7, 34.6, 25.8, 21.6, 20.8, 19.8, 13.8, 8.5. HRMS (ESI) calcd for C48H54NO15 [M+H]+: 884.3493, found 884.3540..

    3'-(N-对三氟甲基苯甲酰基)紫杉醇(14g):白色固体19 mg, 产率50%. m.p. 163~165 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07 (d, J＝7.4 Hz, 2H), 7.78 (d, J＝8.1 Hz, 2H), 7.59 (d, J＝8.1 Hz, 2H), 7.54 (t, J＝7.5 Hz, 1H), 7.47~7.29 (m, 7H), 7.00 (d, J＝8.8 Hz, 1H), 6.20 (s, 1H), 6.16 (d, J＝8.4 Hz, 1H), 5.72 (d, J＝8.9 Hz, 1H), 5.60 (d, J＝7.0 Hz, 1H), 4.87 (d, J＝8.4 Hz, 1H), 4.73 (s, 1H), 4.37~4.28 (m, 1H), 4.24 (d, J＝8.4 Hz, 1H), 4.12 (d, J＝8.4 Hz, 1H), 3.73 (d, J＝6.9 Hz, 1H), 3.43 (s, 1H), 2.53~2.42 (m, 1H), 2.40 (d, J＝3.7 Hz, 1H), 2.31 (s, 3H), 2.28~2.19 (m, 2H), 2.17 (s, 3H), 1.85~1.77 (m, 1H), 1.71 (s, 3H), 1.62 (s, 3H), 1.18 (s, 3H), 1.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.5, 171.6, 170.3, 169.3, 166.0, 164.7, 140.8, 136.6, 135.9, 135.3, 132.8, 132.3, 129.2, 128.1, 127.7, 127.5, 126.5, 126.0, 124.7 (q, J＝3.9 Hz), 83.4, 80.2, 78.1, 76.2, 74.5, 71.9, 71.5, 71.2, 57.6, 54.0, 44.6, 42.2, 34.6, 28.7, 25.9, 21.6, 20.8, 19.8, 13.8, 8.5. HRMS (ESI) calcd for C48H51F3NO14 [M+H]+: 922.3262, found 922.3292..

    3'-(N-对二甲氨基苯甲酰基)紫杉醇(14h):白色固体27 mg, 产率60%. m.p. 166~169 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J＝7.7 Hz, 2H), 7.58 (d, J＝8.7 Hz, 2H), 7.54 (t, J＝7.3 Hz, 1H), 7.44 (t, J＝8.0 Hz, 2H), 7.39 (d, J＝7.8 Hz, 2H), 7.33 (t, J＝7.5 Hz, 2H), 7.26 (t, J＝7.1 Hz, 1H), 6.74 (d, J＝8.6 Hz, 1H), 6.54 (d, J＝8.7 Hz, 2H), 6.20 (s, 1H), 6.13 (t, J＝8.8 Hz, 1H), 5.68 (d, J＝8.6 Hz, 1H), 5.60 (d, J＝6.9 Hz, 1H), 4.88 (d, J＝9.2 Hz, 1H), 4.71 (d, J＝2.5 Hz, 1H), 4.33 (dd, J＝8.9, 8.4 Hz, 1H), 4.22 (d, J＝8.4 Hz, 1H), 4.13 (d, J＝8.3 Hz, 1H), 3.72 (d, J＝6.9 Hz, 1H), 2.93 (s, 6H), 2.54~2.35 (m, 2H), 2.32 (s, 3H), 2.29~2.17 (m, 2H), 2.16 (s, 3H), 1.86~1.79 (m, 1H), 1.73 (s, 3H), 1.61 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 202.7, 171.8, 170.3, 169.4, 166.2, 165.9, 151.8, 141.2, 137.4, 132.7, 132.0, 129.2, 128.2, 127.9, 127.7, 127.6, 127.2, 126.0, 119.0, 110.0, 83.4, 80.1, 78.0, 74.6, 73.9, 72.7, 71.2, 57.6, 54.3, 44.6, 42.2, 39.1, 34.7, 34.6, 25.8, 21.6, 20.9, 19.9, 13.9, 8.5. HRMS (ESI) calcd for C49H57N2O14 [M+H]+: 897.3810, found 897.3781.

    3'-[N-(3, 5-二甲氧基苯甲酰基)]紫杉醇(14i):白色固体17 mg, 产率46%. m.p. 148~149 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.10 (d, J＝7.6 Hz, 2H), 7.54 (t, J＝7.4 Hz, 1H), 7.44 (t, J＝7.4 Hz, 2H), 7.42~7.32 (m, 4H), 7.28 (t, J＝6.9 Hz, 1H), 6.87 (d, J＝8.9 Hz, 1H), 6.76 (s, 2H), 6.48 (s, 1H), 6.20 (s, 1H), 6.18 (t, J＝9.2 Hz, 1H), 5.73 (d, J＝8.7 Hz, 1H), 5.60 (d, J＝7.1 Hz, 1H), 4.87 (d, J＝9.2 Hz, 1H), 4.72 (br.s, 1H), 4.38~4.29 (m, 1H), 4.23 (d, J＝8.3 Hz, 1H), 4.12 (d, J＝8.3 Hz, 1H), 3.74 (d, J＝6.9 Hz, 1H), 3.61 (s, 6H), 3.44 (d, J＝4.6 Hz, 1H), 2.54~2.42 (m, 1H), 2.39 (d, J＝3.7 Hz, 1H), 2.35 (s, 3H), 2.32~2.57 (m, 1H), 2.17 (s, 3H), 1.81 (t, J＝13.2 Hz, 1H), 1.73 (s, 3H), 1.64 (s, 1H), 1.62 (s, 3H), 1.17 (s, 3H), 1.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.6, 171.7, 170.3, 169.4, 166.0, 165.8, 159.9, 141.0, 136.8, 134.8, 132.8, 132.1, 129.3, 128.0, 127.8, 127.3, 125.9, 104.0, 102.7, 83.4, 80.1, 78.2, 74.5, 73.9, 72.2, 71.3, 71.2, 57.6, 54.4, 53.8, 44.6, 42.1, 34.6, 25.8, 21.7, 20.9, 19.9, 13.8, 8.6. HRMS (ESI) calcd for C49H56NO16 [M+H]+: 914.3599, found 914.3552.

    3'-(N-呋喃甲酰基)紫杉醇(14j):白色固体17 mg, 产率49%. m.p. 166~168 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.13 (d, J＝7.5 Hz, 2H), 7.63 (t, J＝7.4 Hz, 1H), 7.57~7.38 (m, 7H), 7.35 (t, J＝7.2 Hz, 1H), 7.16 (d, J＝9.1 Hz, 1H), 7.02 (d, J＝3.5 Hz, 1H), 6.47 (dd, J＝3.4, 1.7 Hz, 1H), 6.27 (s, 1H), 6.24 (t, J＝9.2 Hz, 1H), 5.74 (dd, J＝9.1, 2.1 Hz, 1H), 5.67 (d, J＝7.0 Hz, 1H), 4.94 (d, J＝8.4 Hz, 1H), 4.77 (dd, J＝5.2, 2.6 Hz, 1H), 4.40~4.36 (m, 1H), 4.30 (d, J＝8.5 Hz, 1H), 4.20 (d, J＝8.5 Hz, 1H), 3.80 (d, J＝6.9 Hz, 1H), 3.61 (d, J＝5.3 Hz, 1H), 2.60~2.50 (m, 1H), 2.48 (d, J＝4.0 Hz, 1H), 2.37 (s, 3H), 2.36~2.25 (m, 2H), 2.24 (s, 3H), 1.87~1.84 (m, 1H), 1.81 (s, 3H), 1.69 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 203.6, 172.7, 171.3, 170.4, 167.1, 167.0, 142.0, 138.0, 133.7, 133.6, 133.2, 132.0, 130.2, 129.2, 129.0, 128.8, 128.7, 128.4, 127.1, 127.0, 84.4, 81.2, 79.0, 76.5, 75.6, 74.9, 73.2, 72.3, 72.2, 58.6, 55.1, 45.7, 43.2, 35.7, 35.6, 26.9, 22.6, 21.8, 20.9, 14.8, 9.6. HRMS (ESI) calcd for C45H50NO15 [M+H]+: 844.3180, found 844.3167.

    3'-(N-噻吩甲酰基)紫杉醇(14k):白色固体26 mg, 产率59%. m.p. 135~136 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.12 (d, J＝7.3 Hz, 2H), 7.62 (t, J＝7.4 Hz, 1H), 7.55~7.49 (m, 3H), 7.49~7.43 (m, 3H), 7.41 (t, J＝7.4 Hz, 2H), 7.34 (t, J＝7.1 Hz, 1H), 7.04 (dd, J＝4.9, 3.8 Hz, 1H), 6.93 (d, J＝9.0 Hz, 1H), 6.27 (s, 1H), 6.23 (t, J＝9.1 Hz, 1H), 5.75 (dd, J＝8.9, 2.4 Hz, 1H), 5.67 (d, J＝7.0 Hz, 1H), 4.93 (d, J＝8.3 Hz, 1H), 4.78 (d, J＝2.2 Hz, 1H), 4.39 (dd, J＝10.5, 6.8 Hz, 1H), 4.28 (d, J＝8.4 Hz, 1H), 4.20 (d, J＝8.4 Hz, 1H), 3.88~3.60 (m, 2H), 2.60~2.50 (m, 2H), 2.36 (s, 3H), 2.34~2.24 (m, 2H), 2.23 (s, 3H), 1.87~1.82 (m, 1H), 1.80 (s, 3H), 1.68 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 203.6, 172.6, 171.3, 170.5, 167.0, 161.5, 141.9, 137.9, 133.7, 133.2, 130.8, 130.2, 129.2, 129.0, 128.8, 128.7, 128.4, 127.8, 127.0, 84.4, 81.2, 79.0, 76.5, 75.6, 74.9, 73.2, 72.3, 72.2, 58.6, 55.0, 45.7, 43.2, 35.7, 35.7, 29.7, 22.6, 21.8, 20.9, 14.9, 9.6. HRMS (ESI) calcd for C45H50NO14S [M+H]+: 860.2952, found 860.2914.

    3'-(N-对三氟甲基苯磺酰基)紫杉醇(14m):白色固体14 mg, 产率39%. m.p. 186~188 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, J＝7.5 Hz, 2H), 7.59 (d, J＝8.1 Hz, 2H), 7.53 (t, J＝7.4 Hz, 1H), 7.42– 7.36 (m, 4H), 7.12~7.00 (m, 3H), 6.97 (d, J＝7.2 Hz, 2H), 6.23~6.13 (m, 2H), 6.09 (d, J＝9.2 Hz, 1H), 5.59 (d, J＝7.0 Hz, 1H), 4.97~4.79 (m, 2H), 4.46 (t, J＝4.0 Hz, 1H), 4.34~4.25 (m, 1H), 4.21 (d, J＝8.6 Hz, 1H), 4.13 (d, J＝8.6 Hz, 1H), 3.76~3.61 (m, 2H), 2.49 (d, J＝3.6 Hz, 1H), 2.53~2.38 (m, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 2.17~2.11 (m, 2H), 1.83~1.80 (m, 1H), 1.73 (s, 3H), 1.62 (s, 3H), 1.17 (s, 3H), 1.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.5, 170.3, 170.2, 169.5, 165.9, 140.6, 134.7, 132.8, 132.4, 129.1, 128.1, 127.6, 127.5, 126.4, 126.1, 124.8 (q, J＝3.6 Hz), 83.3, 80.4, 78.0, 74.5, 73.9, 73.5, 71.3, 71.1, 58.8, 57.6, 44.6, 42.1, 34.6, 25.8, 21.6, 20.6, 19.8, 14.0, 8.6. HRMS (ESI) calcd for C47H51F3NO15S [M+H]+: 958.2932, found 958.2947.

    13-[(4S, 5R)-3-对三氟甲基苯磺酰基-2-(4-甲氧基苯基)-4-苯基]-5-噁唑啉羧酸-巴卡汀Ⅲ酯(cyclo-14m):白色固体13 mg, 产率34%. m.p.143~146 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.96 (d, J＝7.7 Hz, 2H), 7.54 (t, J＝7.3 Hz, 1H), 7.45 (d, J＝8.3 Hz, 2H), 7.44~7.23 (m, 11H), 6.79 (d, J＝8.4 Hz, 2H), 6.37 (s, 1H), 6.22 (s, 1H), 6.18 (t, J＝8.7 Hz, 1H), 5.58 (d, J＝7.0 Hz, 1H), 5.37 (d, J＝3.6 Hz, 1H), 4.82 (d, J＝9.1 Hz, 1H), 4.76 (d, J＝3.6 Hz, 1H), 4.36 (dd, J＝10.4, 6.9 Hz, 1H), 4.18 (d, J＝8.4 Hz, 1H), 4.05 (d, J＝8.4 Hz, 1H), 3.76 (s, 3H), 3.71 (d, J＝6.9 Hz, 1H), 2.52~2.41 (m, 1H), 2.20 (s, 3H), 2.17~2.07 (m, 2H), 1.84 (s, 3H), 1.78 (s, 3H), 1.77~1.73 (m, 1H), 1.59 (s, 3H), 1.21 (s, 3H), 1.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 202.6, 170.3, 169.0, 168.3, 166.0, 159.8, 140.9, 140.7, 137.3, 132.8, 132.3, 129.0, 128.4, 128.1, 128.0, 127.8, 127.6, 127.1, 126.4, 126.2, 124.7 (q, J＝3.8 Hz), 112.9, 92.3, 83.4, 81.4, 79.8, 78.3, 74.4, 73.9, 71.1, 70.9, 64.5, 57.5, 54.3, 44.5, 42.1, 34.6, 34.4, 28.7, 25.7, 20.9, 20.7, 19.8, 14.2, 8.5. HRMS (ESI) calcd for C55H56- F3NO16SNa [M+Na]+: 1098.3170, found 1098.3181.

    13-[(4S, 5R)-3-对甲基苯磺酰基-2-(4-甲氧基苯基)-4-苯基]-5-噁唑啉羧酸-巴卡汀Ⅲ酯(cyclo-14n):白色固体14 mg, 产率36%. m.p. 140~142 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J＝7.4 Hz, 2H), 7.63 (t, J＝7.4 Hz, 1H), 7.57~7.44 (m, 6H), 7.39~7.30 (m, 5H), 7.21 (d, J＝8.0 Hz, 2H), 6.93 (d, J＝8.6 Hz, 2H), 6.45 (s, 1H), 6.28 (s, 1H), 6.10 (t, J＝8.7 Hz, 1H), 5.64 (d, J＝7.0 Hz, 1H), 5.25 (d, J＝4.7 Hz, 1H), 4.88 (d, J＝8.8 Hz, 1H), 4.71 (d, J＝4.7 Hz, 1H), 4.47~4.36 (m, 1H), 4.24 (d, J＝8.4 Hz, 1H), 4.11 (d, J＝8.4 Hz, 1H), 3.85 (s, 3H), 3.74 (d, J＝7.0 Hz, 1H), 2.57~2.48 (m, 1H), 2.46 (d, J＝4.0 Hz, 1H), 2.37 (s, 3H), 2.25 (s, 3H), 2.23~2.07 (m, 2H), 1.86 (s, 3H), 1.78 (s, 3H), 1.72 (s, 1H), 1.65 (s, 3H), 1.26 (s, 3H), 1.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 203.6, 171.3, 170.0, 169.2, 167.0, 160.5, 144.4, 142.1, 138.5, 134.5, 133.9, 133.1, 130.1, 129.7, 129.1, 128.9, 128.9, 128.8, 128.7, 128.5, 128.1, 127.3, 113.9, 93.3, 84.4, 82.3, 80.8, 79.4, 75.5, 75.0, 72.2, 71.8, 58.5, 55.4, 45.6, 43.2, 35.6, 29.7, 26.8, 21.9, 21.7, 21.6, 20.9, 15.1, 9.5. HRMS (ESI) calcd for C55H60NO16S [M+H]+: 1022.3633, found 1022.3620.

    3.2.8   13-(N-苯甲酰基)-苯基异丝氨酸-7, 10-二甲氧基-10-去乙酰基巴卡汀Ⅲ酯(15a)的合成

    将化合物11 (0.1 mmol)、化合物9a (0.23 mmol)、二甲氨基吡啶(DMAP, 0.23 mmol)和2.5 mL无水甲苯加入50 mL烧瓶中, 加热至70 ℃使反应液呈悬浊液, 之后加入DCC (0.17 mmol), 反应15 min后再加入DCC (0.16 mmol), 继续搅拌1 h. TCL和LC-MS监测反应, 反应结束后过滤, 收集滤液.最后以V(石油醚):V(乙酸乙酯)＝1:1为洗脱剂柱层析分离得到白色固体13a, 收率为92%.向所得白色固体13a中(0.1 mmol)中加入3 mL无水乙醇, 呈白色浊液, 再向反应液中加入20%~30%的HCl/EtOH溶液0.5 mL, 室温下搅拌24 h, 反应液澄清. LC-MS监测反应, 反应结束后加入1.5 mL饱和NaHCO3溶液、0.5 mL水和10 mL乙酸乙酯萃取分液, 水相再用10 mL乙酸乙酯反萃, 合并乙酸乙酯相, 干燥浓缩.最后以V(二氯甲烷):V(甲醇)＝20:1为洗脱剂柱层析分离得到42 mg白色固体15a, 收率为55%. m.p. 221~222 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J＝7.7 Hz, 2H), 7.71 (d, J＝7.7 Hz, 2H), 7.53 (t, J＝7.2 Hz, 1H), 7.49~7.38 (m, 5H), 7.37~7.31 (m, 4H), 7.27 (t, J＝7.2 Hz, 1H), 7.06 (d, J＝8.7 Hz, 1H), 6.12 (t, J＝8.7 Hz, 1H), 5.72 (d, J＝8.8 Hz, 1H), 5.56 (d, J＝6.8 Hz, 1H), 4.90 (d, J＝9.4 Hz, 1H), 4.74~4.70 (m, 1H), 4.69 (s, 1H), 4.22 (d, J＝8.4 Hz, 1H), 4.11 (d, J＝8.4 Hz, 1H), 3.82~3.68 (m, 2H), 3.58 (d, J＝4.8 Hz, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 2.67~2.57 (m, 1H), 2.30 (s, 3H), 2.26~2.15 (m, 2H), 1.78~1.71 (m, 1H), 1.70 (s, 3H), 1.65 (s, 3H), 1.60 (s, 1H), 1.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ: 203.9, 171.4, 169.6, 165.9, 137.3, 137.0, 134.9, 132.7, 132.6, 130.9, 129.1, 128.2, 128.0, 127.7, 127.3, 126.1, 126.1, 99.0, 83.1, 81.6, 80.8, 79.8, 77.7, 73.5, 72.3, 71.5, 59.4, 56.4, 56.0, 55.9, 54.0, 46.4, 42.2, 34.4, 31.1, 30.9, 28.7, 25.9, 21.7, 19.6, 13.6, 13.2, 13.1, 9.3. HRMS (ESI) calcd for C47H54NO13 [M+H]+: 840.3595, found 840.3544.

    13-(N-对二甲氨基苯甲酰基)苯基异丝氨酸-7, 10-二甲氧基-10-去乙酰基巴卡汀Ⅲ酯(15h):白色固体19 mg, 产率56%. m.p. 232~234 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J＝7.7 Hz, 2H), 7.61 (d, J＝8.7 Hz, 2H), 7.54 (t, J＝7.3 Hz, 1H), 7.46~7.36 (m, 4H), 7.32 (t, J＝7.3 Hz, 2H), 7.24 (t, J＝7.9 Hz, 1H), 6.91 (d, J＝8.7 Hz, 1H), 6.55 (d, J＝8.6 Hz, 2H), 6.09 (t, J＝8.6 Hz, 1H), 5.68 (d, J＝7.9 Hz, 1H), 5.55 (d, J＝6.9 Hz, 1H), 4.90 (d, J＝9.2 Hz, 1H), 4.75~4.64 (m, 2H), 4.22 (d, J＝8.3 Hz, 1H), 4.10 (d, J＝8.3 Hz, 1H), 3.81~3.66 (m, 2H), 3.35 (s, 3H), 3.21 (s, 3H), 2.93 (s, 6H), 2.67~2.55 (m, 1H), 2.31 (s, 3H), 2.23~2.10 (m, 2H), 1.80~1.73 (m, 1H), 1.71 (s, 3H), 1.68 (s, 1H), 1.64 (s, 3H), 1.11 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 205.0, 172.6, 170.6, 167.1, 166.9, 152.7, 138.7, 138.4, 135.6, 133.7, 130.2, 129.2, 128.9, 128.7, 128.1, 127.5, 120.1, 111.0, 84.1, 82.6, 81.7, 80.8, 78.7, 77.4, 77.1, 76.7, 76.6, 74.5, 73.8, 72.3, 57.3, 57.1, 56.9, 55.2, 47.4, 43.2, 40.1, 35.5, 32.1, 26.9, 22.7, 20.7, 14.6, 10.4. HRMS (ESI) calcd for C49H59N2O13 [M+H]+: 883.4017, found 883.4048.

    13-[N-(2-呋喃甲酰基)]-苯基异丝氨酸-7, 10-二甲氧基-10-去乙酰基巴卡汀Ⅲ酯(15j):白色固体20 mg, 产率54%. m.p. 235~236 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J＝7.5 Hz, 2H), 7.54 (t, J＝7.4 Hz, 1H), 7.48~7.37 (m, 5H), 7.33 (t, J＝7.4 Hz, 2H), 7.26 (t, J＝7.2 Hz, 1H), 7.18 (d, J＝3.5 Hz, 1H), 6.99 (d, J＝3.3 Hz, 1H), 6.41 (dd, J＝3.2, 1.5 Hz, 1H), 6.13 (t, J＝8.5 Hz, 1H), 5.68 (dd, J＝9.1, 2.2 Hz, 1H), 5.55 (d, J＝6.9 Hz, 1H), 4.89 (d, J＝9.0 Hz, 1H), 4.73~4.65 (m, 2H), 4.21 (d, J＝8.4 Hz, 1H), 4.12 (d, J＝8.4 Hz, 1H), 3.81~3.70 (m, 2H), 3.62 (d, J＝4.9 Hz, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 2.67~2.56 (m, 1H), 2.28 (s, 3H), 2.22~2.15 (m, 2H), 1.80~1.74 (m, 1H), 1.73 (s, 3H), 1.65 (s, 3H), 1.61 (s, 1H), 1.12 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 204.8, 172.1, 170.6, 166.9, 157.8, 147.4, 144.2, 138.3, 137.9, 135.9, 133.6, 130.2, 129.3, 128.9, 128.6, 128.3, 127.2, 115.1, 112.3, 84.1, 82.7, 81.9, 80.8, 78.7, 77.3, 77.0, 76.7, 74.5, 73.5, 72.4, 57.4, 57.0, 54.3, 47.5, 43.3, 35.4, 32.2, 27.0, 22.7, 20.6, 14.6, 10.3. HRMS (ESI) calcd for C45H51NO14Na [M+Na]+: 852.3207, found 852.3229.

    13-[N-(2-噻吩甲酰基)]-苯基异丝氨酸-7, 10-二甲氧基-10-去乙酰基巴卡汀Ⅲ酯(15k):白色固体23 mg, 产率57%. m.p. 230~231 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.03 (d, J＝7.7 Hz, 2H), 7.53 (t, J＝7.3 Hz, 1H), 7.49~7.37 (m, 6H), 7.33 (t, J＝7.3 Hz, 2H), 7.27 (t, J＝7.3 Hz, 1H), 6.99 (t, J＝4.2 Hz, 1H), 6.90 (d, J＝8.9 Hz, 1H), 6.13 (t, J＝8.6 Hz, 1H), 5.69 (d, J＝8.9 Hz, 1H), 5.55 (d, J＝6.8 Hz, 1H), 4.89 (d, J＝9.3 Hz, 1H), 4.75~4.66 (m, 2H), 4.21 (d, J＝8.3 Hz, 1H), 4.12 (d, J＝8.3 Hz, 1H), 3.81~3.69 (m, 2H), 3.61 (d, J＝4.4 Hz, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 2.67~2.56 (m, 1H), 2.28 (s, 3H), 2.24~2.13 (m, 2H), 1.79~1.72 (m, 1H), 1.71 (s, 3H), 1.65 (s, 3H), 1.60 (s, 1H), 1.12 (s, 6H); 13C NMR (101 MHz, CDCl3) δ: 203.8, 171.2, 169.7, 165.94, 160.3, 137.2, 137.1, 136.9, 135.0, 132.6, 129.6, 129.1, 128.3, 127.9, 127.7, 127.6, 127.3, 126.7, 126.1, 83.1, 81.7, 80.9, 79.8, 77.7, 76.3, 76.0, 75.7, 73.5, 72.4, 71.5, 56.4, 56.0, 53.9, 46.5, 42.3, 34.5, 31.2, 26.0, 21.7, 19.6, 13.6, 9.3. HRMS (ESI) calcd for C45H51NO13SNa [M+Na]+: 868.2979, found 868.2970.

    辅助材料(Supporting Information)  化合物7a~7o、化合物8a~8o、化合物14b, 14e~14m、化合物15a、15h、15j、15k的核磁共振氢谱、碳谱谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

    1. [1]

      (a) Yu, Y.; Wang, J. F.; Wang, C. Y.; Li, Y. X. Chin. J. Mod. Appl. Pharm. 2012, 29, 16 (in Chinese).
      (于跃, 王军飞, 王长云, 李英霞, 中国现代应用药学, 2012, 29, 16.)
      (b) Sheng, J. J. M.S. Thesis, East China Normal University, Shanghai, 2018 (in Chinese).
      (盛家骏, 硕士论文, 华东师范大学, 上海, 2018.

    2. [2]

      Rowinsky, E. K. Annu. Rev. Med. 1997, 48, 353-374. doi: 10.1146/annurev.med.48.1.353

    3. [3]

      史清文, 中草药, 2011, 42, 1878. http://www.cnki.com.cn/Article/CJFDTotal-ZCYO201110004.htmShi, Q. W. Chin. Tradit. Herb. Drugs 2011, 42, 1878 (in Chinese). http://www.cnki.com.cn/Article/CJFDTotal-ZCYO201110004.htm

    4. [4]

      (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1994, 367, 630.
      (b) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed. 1994, 33, 15.
      (c) Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994, 116, 1597.
      (d) Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Grandi, M. J. D. J. Am. Chem. Soc. 1996, 118, 2843.
      (e) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass, T. E.; Houze, J. B.; Crauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997, 119, 2755.
      (f) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980.
      (g) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.; Yamada, K.; Saitoh, K. Chem.-Eur. J. 1999, 5, 121.
      (h) Doi, T.; Fuse S.; Miyamoto, S.; Nakai, K.; Sasuga, D.; Takahashi, T. Chem.-Asian J. 2006, 1, 370.

    5. [5]

      (a) Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Acc. Chem Res. 1993, 26, 160.
      (b) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 34, 6985.

    6. [6]

      (a) Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J. J. Org. Chem. 1986, 51, 46.
      (b) Deng, L.; Jacobson, E. N. J. Org. Chem. 1992, 57, 4320.
      (c) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451.

    7. [7]

      Sharpless, K. B.; Wang, Z. M.; Kolb, H. C. J. Org. Chem. 1994, 59, 5104. doi: 10.1021/jo00096a072

    8. [8]

      (a) Liu, W.; Lv, B.; Gong, L. Angew. Chem., Int. Ed. 2009, 48, 6503.
      (b) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
      (c) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420.
      (d) Olofsson, B.; Somfai, P. J. Org. Chem. 2002, 67, 8574.
      (e) Hu, X. E. Tetrahedron 2004, 60, 2701.

    9. [9]

      (a) Qian, Y.; Xu, X. F.; Jiang, L. Q.; Prajapati, D.; Hu, W. H. J. Org. Chem. 2010, 75, 7483.
      (b) Guo, Z. Q.; Shi, T. D.; Jiang, J.; Yang, L. P.; Hu, W. H. Org. Biomol. Chem. 2009, 7, 5028.

    10. [10]

      (a) Torssell, S.; Kienle, M.; Somfai, P. Angew. Chem., Int. Ed. 2005, 44, 3096.
      (b) Torssell, S.; Somfai, P. Adv. Synth. Catal. 2006, 348, 2421.
      (c) Sheng, J. J.; Chang, H.; Qian, Y.; Ma, M. L.; Hu, W. H. Tetrahedron Lett. 2018, 59, 2141.

    11. [11]

      Xu, X. F.; Guo, X.; Han, X. C.; Yang, L. P.; Hu, W. H. Org. Chem. Front. 2014, 1, 181. doi: 10.1039/c3qo00040k

    12. [12]

      Verkade, J.; Van Hemert, L.; Quaedflieg, P.; Alsters, P.; Van Delft, F.; Rutjes, F. Tetrahedron Lett. 2006, 47, 8109.
      Li, Q. F.; Lin, H. X.; Cui, Y. M.; Xu, P. P. Eur. J. Med. Chem. 2015, 104, 97.

  • 图式 1  紫杉醇的半合成

    Scheme 1  Semi-synthesis of paclitaxel

    下载: 全尺寸图片 幻灯片

    图式 2  噁唑烷型侧链合成路线

    Scheme 2  Synthesis route of oxazoline type side chain

    下载: 全尺寸图片 幻灯片

    图式 3  底物拓展

    Scheme 3  Scope extension of the substrate

    下载: 全尺寸图片 幻灯片

    图式 4  紫杉醇衍生物的合成

    Scheme 4  Synthesis of the paclitaxel analogues

    下载: 全尺寸图片 幻灯片

    表 1  金属催化剂的筛选a

    Table 1.  Selection of metal catalysis

    Entry Catalyst x/mol% Yieldb/% drc(syn:anti)
    1 Rh2(OAc)4 2 62 58:42
    2 Cu(OTf)2 10.0 57 44:56
    3 Cu(OTf)2 5.0 58 45:55
    4 Cu(OTf)2 2.0 52 45:55
    5 Cu(OTf)2+p-TsOH 5.0,
    10.0    		 60 38:62
    6 Cu(OTf)2+AgPF6 5.0,
    10.0    		 46 52:48
    7 Cu(CH3CN)4BF4 5.0 43 41:59
    8 Cu(AcAc)2 5.0 — —
    9 CuSO4 5.0 — —
    10 FeCl2 5.0 — —
    11 Fe(OTf)3 5.0 — —
    a The reaction was carried out with aniline 3a (1 equiv.), aldehyde 4a (1.05 equiv.), H2O (3 equiv.) and catalyst (2.0~20.0 mol%) in CH2Cl2 at room temperature with addition of EDA 2 (1.5 equiv.) over 1h. b Isolated yield (two diastereoisomers). c Determined by 1H NMR spectroscopy of the crude reaction mixture.
    下载: 导出CSV

    表 2  溶剂与温度的筛选

    Table 2.  Optimization of solvent and temperaturea

    Entry Solvent Temp./℃ Yieldb/% drc(syn:anti)
    1 CH2Cl2 0 53 45:55
    2 CH2Cl2 Reflux 47 43:57
    3 THF 25 ＜10 —
    4 CHCl3 25 54 42:58
    5 CH3CN 25 — —
    6 EtOAc 25 45 37:63
    7 Hexane 25 34 46:54
    8 Toluene 25 30 44:56
    9d CH2Cl2 25 56 45:55
    a The reaction was carried out with aniline 3a (1 equiv.), aldehyde 4a (1.05 equiv.), H2O (3 equiv.) and Cu(OTf)2 (5.0 mol%) in the solvent with addition of EDA 2 (1.5 equiv.) over 1 h. b Isolated yield (two diastereoisomers). c Determined by 1H NMR spectroscopy of the crude reaction mixture. d The reaction was carried out on 10 g scale.
    下载: 导出CSV

    表 3  紫杉醇衍生物的抗肿瘤细胞活性a

    Table 3.  Anti-tumor activity of the paclitaxel analogues

    Entry Mr IC50/(μmol·L－1)
    H460 MG63 KB PC9
    Paclitaxel 853.33 0.0119 0.0115 0.0006 0.0031
    anti-14b 888.36 ＞50 ＞50 9.6593 30.6455
    14e 883.34 0.0203 0.0218 0.0004 0.0064
    14h 896.37 0.0152 0.0455 0.0022 0.0145
    14i 913.35 0.1551 0.2918 0.0594 0.0930
    14j 843.31 0.0046 0.0059 0.0005 0.0046
    14k 859.29 0.0037 0.0014 ＜0.0005 0.0010
    14m 957.29 13.7922 20.3900 6.0461 13.7886
    Cyclo-14m 1075.33 ＞50 ＞50 ＞50 ＞50
    Cyclo-14n 1021.36 ＞50 ＞50 30.4081 ＞50
    Cabazitaxel 835.38 ＜0.0005 0.0080 ＜0.0005 ＜0.0005
    15a 839.35 0.0179 0.0029 ＜0.0005 0.0012
    15h 882.39 0.0018 0.0046 ＜0.0005 0.0017
    a The data provided by collaborators from School of Pharmaceutical Sciences, Sun Yat-sen University.
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  • 发布日期:  2019-02-25
  • 收稿日期:  2018-07-24
  • 修回日期:  2018-12-17
  • 网络出版日期:  2018-02-21
通讯作者: 陈斌, bchen63@163.com
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