CN109776571B - 一种雷帕霉素类似物及其制备方法和应用 - Google Patents
一种雷帕霉素类似物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种雷帕霉素类似物及其制备方法和应用。通过以雷帕霉素，重氮化合物和各种亲电试剂为原料，反应得到本发明雷帕霉素类似物。本发明制备路线短，操作安全简单，便于获得雷帕霉素类似物，提供多样性化合物骨架，可广泛应用于新药筛选和制药领域。
Description
技术领域
本发明属于新药合成技术领域，具体涉及一种雷帕霉素类似物及其制备方法和应用。
背景技术
癌症是世界医学界公认的“死亡杀手”，国际癌症研究机构发表的《2018年世界癌症报告》显示，报告显示，2018年全球新增1810万例癌症病例，死亡人数达960万，全球癌症负担进一步加重。随着国内自然环境的恶化、空气污染的加重，癌症的死亡率居高不下，已经超过心脑血管疾病，成为人们生命健康最大的威胁。发展高效的抗癌药物已经迫在眉睫。随着科学技术的迅猛发展及分子肿瘤学、分子生物学技术的进步，新型抗肿瘤药物不断涌现，抗癌药物的研究与开发已进入一个崭新的阶段。
天然产物一直是小分子药物和化学探针的主要来源。其中雷帕霉素(Rapamycin)及其半合成衍生物可作为免疫抑制剂，抗癌药或抗衰老剂。哺乳动物的雷帕霉素靶蛋白(mTOR)作为蛋白质复合物1(mTORC1)和复合物2(mTORC2)的催化亚基，两者均调节细胞和生物体的多种生物学过程。其中，PIK3CA-AKT-mTOR途径在许多人类癌症中被强烈激活，这推动治疗晚期肾细胞癌的temsirolimus和依维莫司的发现。雷帕霉素通过雷帕霉素-FKBP12复合物有效抑制mTORC1，而其治疗时间的延长将消除mTORC2信号传导，从而损害葡萄糖体内平衡和免疫系统。然而，temsirolimus和依维莫司有效抑制mTORC1，同时对雷帕霉素的葡萄糖稳态影响较小。这些结果表明雷帕霉素C-40上羟基的修饰会产生功能类似物，以调节mTORC1和mTORC2的信号传导强度，通过抑制两种复合物可以减少副作用。由于其高度复杂的分子结构，许多其他雷帕霉素衍生物也已经通过半合成或生物合成方法制备。因此我们推断，基于我们之前利用20,000L发酵罐从Streptomyces hygroscopicus突变菌株中高产量生产的雷帕霉素，在C-40上进一步衍生雷帕霉素将提供一种获得功能类似物的通用方法。以雷帕霉素为中间体半合成研究以期获得更为理想的药物动力学性质和新型抗癌活性的化合物。
发明内容
本发明旨在克服现有技术的不足，提供针对现有技术的上述不足，提供一种雷帕霉素类似物及其制备方法和应用。
为了达到上述目的，本发明提供的技术方案为：
所述雷帕霉素类似物的化学结构如式(I)所示：
式(I)
其中，R1为取代的芳香基团；R2为甲氧基；X为氧；R3为氢、不同取代位置的氟、氯、溴、甲氧基、三氟甲基；R4为氢、苄基。
优选地，R1为苯基、3-甲氧基苯基、4-氟苯基、3-氟苯基、4-氯苯基。
优选地，所述方法包括以下步骤：以雷帕霉素、重氮化合物和取代靛红为原料，以金属盐为催化剂，反应得到式(I)所示的化合物，反应式如下：
其中，所述金属盐为醋酸铑、辛酸铑、三氟甲磺酸铜、三氟甲磺酸亚铜、硫酸铜或氯化丁烯钯二聚体；所述溶剂为二氯甲烷、三氯甲烷、四氯甲烷、1,2-二氯乙烷、甲苯、乙酸乙酯中的至少一种；其中，雷帕霉素、重氮化合物、取代靛红、催化剂之间的摩尔比为 1.0:(1.0-10.0):(1.0-10.0):(0.001-0.1)。
优选地，所述雷帕霉素、重氮化合物、取代靛红、催化剂之间的摩尔比为1.0:(2.0-5.0): (2.0-5.0):(0.01-0.1)。
本发明还提供了雷帕霉素类似物在抗肿瘤细胞活性中的应用。实例表明，合成的部分新型雷帕霉素类似物表现出对肿瘤细胞株(HeLa)的抑制活性，可作为有效的抗肿瘤化合物应用于医药领域。本发明提供雷帕霉素类似物在抗肿瘤方面的应用。
本发明具有优点及有益效果为：合成制备路线短，操作简单，成本低，大大提高原料利用率。本发明能简单快捷地合成新型雷帕霉素类似物，从而提供多样性的雷帕霉素类似物，对新药筛选和制药工艺具有非常重要的意义。
附图说明
图1为雷帕霉素及其类似物浓度为5nM时对A549细胞系的细胞毒性；
图2为雷帕霉素及其类似物对A549(A)细胞系的IC50测定结果；
图3为雷帕霉素及其类似物对SKBR3细胞系的IC50测定结果。
具体实施方式
结合以下具体实施例，对本发明作进一步详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明 中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。
实施例1：称取雷帕霉素(0.05mmol)、靛红3a(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-a，收率93％。
产物I-a结构式为：
I-a表征为：1H NMR(500MHz,CDCl3)δ7.88(s,1H),7.55(s,2H),7.21(d,J＝6.4Hz,1H), 7.16(s,2H),7.06(m,1H),6.83(d,J＝6.8Hz,1H),6.51(dd,J＝14.9,7.9Hz,1H),6.39(t,J＝ 12.3Hz,2H),6.30(m,1H),6.14(dd,J＝14.7,10.1Hz,1H),5.97(d,J＝10.4Hz,1H),5.53(m, 1H),5.42(t,J＝10.0Hz,1H),5.28(s,1H),5.12(dd,J＝29.0,4.3Hz,1H),4.77(d,J＝21.1Hz, 1H),4.19(m,1H),3.86(m,2H),3.81(s,3H),3.76(m,1H),3.67(dd,J＝16.2,8.8Hz,1H),3.58 (s,1H),3.54(d,J＝11.8Hz,1H),3.46(s,1H),3.40(d,J＝13.3Hz,3H),3.37(s,1H),3.34(d,J ＝13.7Hz,3H),3.31(m,1H),3.13(d,J＝8.4Hz,3H),2.70(d,J＝11.4Hz,2H),2.63–2.53(m, 1H),2.38–2.26(m,2H),2.14(d,J＝12.4Hz,1H),2.00(s,2H),1.92(s,1H),1.86(m,1H), 1.84(m,1H),1.77(m,4H),1.73(s,1H),1.68(d,J＝22.1Hz,4H),1.60(d,J＝9.9Hz,3H), 1.48(s,1H),1.46(s,2H),1.40(s,1H),1.32(m,1H),1.26(s,1H),1.20(d,J＝10.7Hz,1H), 1.15(d,J＝6.2Hz,1H),1.09(d,J＝6.4Hz,3H),1.07–1.01(m,4H),0.99(d,J＝5.9Hz,3H), 0.95(d,J＝6.3Hz,3H),0.90(d,J＝6.4Hz,3H),0.67(m,1H)；
13C NMR(126MHz,CDCl3)δ215.28,208.25,192.79,177.56,172.07,169.28,166.76,141.07, 140.01,136.02,135.68,133.54,132.86,130.20,130.17,129.48,128.93,127.80,127.09,126.84, 126.60,126.54,126.48,122.02,109.20,98.51,85.70,84.88,84.32,82.98,81.75,77.76,77.04, 75.66,67.19,59.26,56.66,55.86,52.64,51.28,46.57,44.21,41.45,40.71,40.22,38.94,38.11, 35.31,35.09,33.81,33.19,31.74,31.21,30.69,27.22,27.03,25.26,21.47,20.63,16.22,15.94, 15.87,13.69,13.22,10.18；
HRMS(ESI)m/z calcd for C68H92N2NaO17,[M+Na]+1231.6293；Found:1231.6284.
实施例2：称取雷帕霉素(0.05mmol)、靛红3a(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2b(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-b，收率87％。
产物I-b结构式为：
I-b表征为：1H NMR(500MHz,CDCl3)δ7.80(s,1H),7.52(s,2H),7.33(s,1H),7.09(t,J＝ 7.4Hz,1H),6.89(t,J＝7.3Hz,1H),6.79(t,J＝15.1Hz,2H),6.52(d,J＝7.3Hz,1H),6.43– 6.35(m,1H),6.34–6.27(m,1H),6.24(d,J＝14.5Hz,1H),6.14(dd,J＝14.8,10.0Hz,1H), 5.94(dd,J＝39.0,10.6Hz,1H),5.60–5.46(m,1H),5.42(d,J＝9.9Hz,1H),5.27(d,J＝4.5 Hz,1H),5.16(s,1H),4.75(d,J＝22.7Hz,1H),4.24–4.16(m,1H),3.88(s,1H),3.86(s,3H), 3.77(d,J＝4.9Hz,1H),3.74–3.69(m,1H),3.67(t,J＝7.3Hz,1H),3.59(d,J＝7.3Hz,1H), 3.54(d,J＝13.5Hz,1H),3.42(s,1H),3.37(s,3H),3.33(s,5H),3.13(d,J＝8.6Hz,3H),2.74– 2.67(m,2H),2.63–2.53(m,1H),2.34(s,1H),2.32(s,1H),2.14(d,J＝12.1Hz,1H),1.97(d, J＝5.4Hz,4H),1.90–1.82(m,2H),1.77(d,J＝7.1Hz,4H),1.73(s,1H),1.67(d,J＝15.1Hz, 4H),1.62(d,J＝14.4Hz,3H),1.46(d,J＝6.8Hz,2H),1.43(d,J＝6.2Hz,1H),1.40(s,1H), 1.32(d,J＝6.8Hz,1H),1.30(s,1H),1.21(d,J＝9.4Hz,1H),1.16(s,1H),1.15(s,1H),1.09(d, J＝6.4Hz,3H),1.07–1.02(m,4H),0.99(d,J＝5.8Hz,3H),0.95(d,J＝6.2Hz,3H),0.91(d, J＝6.2Hz,3H),0.73–0.62(m,1H)；
13C NMR(126MHz,CDCl3)δ215.30,208.23,192.78,177.34,171.92,169.30,166.76,140.72, 140.01,136.01,135.74,133.53,132.19,130.22,129.70,129.45,128.75,127.51,127.21,126.60, 126.49,122.16,113.63,113.46,109.30,98.51,86.31,84.84,84.32,82.95,81.91,77.91,75.61, 67.20,59.28,56.60,55.87,52.81,51.28,46.57,44.22,41.48,40.65,40.22,38.97,38.12,35.38, 35.11,33.82,33.17,31.73,31.22,30.57,27.22,27.04,25.26,21.47,20.64,16.21,15.92,15.90, 13.66,13.24,10.18；
HRMS(ESI)m/z calcd for C68H91FN2NaO17,[M+Na]+1249.6199；Found:1249.6154.
实施例3：称取雷帕霉素(0.05mmol)、靛红3a(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2c(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-c，收率85％。
产物I-c结构式为：
I-c表征为：1H NMR(500MHz,CDCl3)δ7.78(s,1H),7.46(t,J＝13.4Hz,2H),7.41–7.31 (m,1H),7.09(t,J＝8.6Hz,3H),6.97–6.84(m,1H),6.51(d,J＝7.3Hz,1H),6.46–6.35(m, 1H),6.35–6.28(m,1H),6.23(d,J＝12.7Hz,1H),6.15(dd,J＝14.8,10.0Hz,1H),5.94(dd,J ＝39.5,10.6Hz,1H),5.62–5.46(m,1H),5.42(d,J＝9.9Hz,1H),5.34–5.23(m,1H),5.13 (dd,J＝34.1,11.5Hz,1H),4.78(s,1H),4.20(d,J＝5.2Hz,1H),3.86(s,3H),3.77(d,J＝5.1 Hz,1H),3.71(d,J＝5.1Hz,1H),3.67(t,J＝7.3Hz,1H),3.57(d,J＝12.9Hz,1H),3.43(s,1H), 3.39(s,1H),3.34(s,3H),3.32(d,J＝12.9Hz,3H),3.14(d,J＝7.9Hz,3H),2.77–2.65(m, 2H),2.58(dd,J＝16.7,6.1Hz,1H),2.35(s,1H),2.33(s,1H),2.14(d,J＝12.6Hz,1H),2.00(d, J＝5.2Hz,1H),1.93(s,2H),1.88–1.82(m,1H),1.76(s,4H),1.73(s,1H),1.66(s,4H),1.64– 1.57(m,3H),1.49(s,1H),1.47(s,2H),1.43(d,J＝7.5Hz,1H),1.36(s,1H),1.30(s,1H),1.27 (s,1H),1.20(s,1H),1.16(s,1H),1.15(s,1H),1.09(d,J＝6.4Hz,3H),1.07–1.02(m,4H), 1.00(d,J＝5.8Hz,3H),0.96(d,J＝6.3Hz,3H),0.91(d,J＝6.3Hz,3H),0.68(dd,J＝23.2, 11.4Hz,1H).
13C NMR(126MHz,CDCl3)δ215.27,208.25,192.82,177.30,171.70,169.31,166.76,140.66, 139.99,136.00,134.03,133.52,131.71,131.54,130.22,129.79,129.72,129.43,127.35,127.25, 126.79,126.57,126.51,122.22,109.42,98.52,86.32,84.85,84.31,82.95,81.92,78.09,75.59, 67.20,59.26,56.58,55.87,52.86,51.29,46.58,44.23,41.50,40.63,40.23,38.98,38.15,35.42, 35.09,33.83,33.19,31.92,31.70,31.22,30.60,27.23,27.04,25.26,21.47,20.65,16.22,15.93, 15.89,13.65,13.27,10.19；
HRMS(ESI)m/z calcd for C68H91ClN2NaO17,[M+Na]+1265.5903；Found:1265.5860.
实施例4：称取雷帕霉素(0.05mmol)、靛红3a(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2d(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-d，收率70％。
产物I-d结构式为：
I-d表征为：1H NMR(500MHz,CDCl3)δ7.98(d,J＝13.3Hz,1H),7.39(dd,J＝34.2,8.8Hz, 2H),7.26(d,J＝8.1Hz,1H),7.07(d,J＝7.3Hz,2H),6.91(dd,J＝17.9,10.4Hz,1H),6.86(d, J＝7.4Hz,1H),6.51(d,J＝7.6Hz,1H),6.44–6.34(m,1H),6.34–6.26(m,1H),6.20(t,J＝ 19.1Hz,1H),6.16–6.08(m,1H),5.94(dd,J＝40.3,10.7Hz,1H),5.60–5.46(m,1H),5.42(d, J＝9.9Hz,1H),5.27(s,1H),5.16(d,J＝4.3Hz,1H),4.77(s,1H),4.20(d,J＝5.0Hz,1H), 3.86(s,4H),3.79(d,J＝4.5Hz,2H),3.74–3.69(m,1H),3.67(t,J＝7.4Hz,1H),3.57(d,J＝ 13.8Hz,1H),3.47(s,1H),3.42(s,1H),3.37(s,1H),3.33(s,6H),3.29(s,1H),3.13(d,J＝9.8 Hz,3H),2.69(d,J＝11.5Hz,2H),2.58(dd,J＝16.7,6.5Hz,1H),2.35(d,J＝3.8Hz,1H),2.32 (s,1H),2.14(d,J＝12.7Hz,2H),2.00(d,J＝4.9Hz,1H),1.98(d,J＝6.4Hz,1H),1.94(s,1H), 1.88–1.84(m,1H),1.76(s,4H),1.73(s,1H),1.66(s,4H),1.62–1.56(m,3H),1.47(s,2H), 1.45(s,1H),1.43(s,1H),1.33(s,1H),1.30(d,J＝6.2Hz,1H),1.20(s,1H),1.16(s,1H),1.14 (s,1H),1.08(d,J＝6.5Hz,3H),1.07–1.02(m,4H),0.99(d,J＝6.1Hz,3H),0.95(d,J＝6.3 Hz,3H),0.91(d,J＝6.4Hz,3H),0.69(dd,J＝22.5,10.6Hz,1H)；
13C NMR(126MHz,CDCl3)δ215.09,208.27,192.92,177.38,171.49,169.31,166.75,162.41, 160.47,140.73,139.92,138.58,135.97,133.49,130.23,129.77,129.38,127.96,127.34,127.20, 126.54,126.48,125.60,122.23,109.39,98.52,86.40,84.88,84.28,82.91,81.95,78.26,75.59, 67.20,59.15,56.49,55.86,52.85,51.30,46.58,44.23,41.50,40.66,40.23,39.01,38.17,35.38, 35.05,33.85,33.24,31.73,31.19,30.68,27.20,27.03,25.25,21.44,20.65,16.20,15.92,15.84, 13.61,13.34,10.19；
HRMS(ESI)m/z calcd for C68H91FN2NaO17,[M+Na]+1249.6199；Found:1249.6146.
实施例5：称取雷帕霉素(0.05mmol)、靛红3a(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2e(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-e，收率75％。
产物I-e结构式为：
I-e表征为：1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.46–7.32(m,1H),7.24(d,J＝9.8Hz, 1H),7.13–7.01(m,3H),6.97–6.82(m,1H),6.72(s,1H),6.50(d,J＝7.4Hz,1H),6.44–6.35 (m,2H),6.35–6.25(m,1H),6.14(dd,J＝14.7,10.1Hz,1H),5.93(dd,J＝40.0,10.6Hz,1H), 5.61–5.47(m,1H),5.42(d,J＝9.9Hz,1H),5.28(d,J＝4.5Hz,1H),5.12(dd,J＝33.4,12.5 Hz,1H),4.79(s,1H),4.25–4.16(m,1H),3.85(s,4H),3.82(s,1H),3.77(d,J＝5.2Hz,1H), 3.73–3.64(m,1H),3.59(s,3H),3.56(s,1H),3.53–3.46(m,1H),3.43(s,3H),3.38(d,J＝8.5 Hz,2H),3.33(s,3H),3.13(d,J＝14.4Hz,3H),2.70(dd,J＝15.9,5.2Hz,2H),2.58(dd,J＝ 16.7,6.2Hz,1H),2.33(d,J＝12.2Hz,2H),2.18(d,J＝11.7Hz,1H),1.99(s,4H),1.86–1.82 (m,1H),1.76(d,J＝6.6Hz,5H),1.73(s,1H),1.66(s,4H),1.64–1.57(m,3H),1.48(s,1H), 1.47(s,2H),1.43(s,1H),1.41(d,J＝8.0Hz,1H),1.32(d,J＝5.9Hz,1H),1.30(d,J＝5.3Hz, 1H),1.20(d,J＝9.9Hz,1H),1.16(s,1H),1.15(s,1H),1.09(d,J＝6.4Hz,3H),1.05(dd,J＝ 11.9,6.5Hz,4H),0.99(d,J＝6.1Hz,3H),0.95(d,J＝6.3Hz,3H),0.91(d,J＝6.4Hz,3H), 0.68(dd,J＝23.9,12.0Hz,1H).
13C NMR(126MHz,CDCl3)δ215.29,208.28,192.78,177.48,172.34,169.29,166.77,158.23, 140.96,140.01,136.01,135.71,133.98,133.54,130.19,129.60,129.45,127.80,127.64,127.38, 126.54,126.49,122.84,121.93,115.26,114.94,109.27,98.50,86.39,84.90,84.31,83.05,81.90, 77.61,75.64,67.19,59.23,56.55,55.87,55.28,52.72,51.30,46.58,44.23,41.47,40.64,40.22, 38.95,38.18,35.31,35.07,33.80,33.17,31.75,31.21,30.45,27.22,27.03,25.26,21.46,20.65, 16.22,15.94,15.80,13.68,13.27,10.18；
HRMS(ESI)m/z calcd for C69H94N2NaO18,[M+Na]+1261.6399；Found:1261.6352.
实施例6：称取雷帕霉素(0.05mmol)、靛红3c(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-f，收率76％。
产物I-f结构式为：
I-f表征为：1HNMR(500MHz,CDCl3)δ7.96(d,J＝16.2Hz,1H),7.54(s,1H),7.16(s,3H), 7.13–7.07(m,1H),6.99(d,J＝32.6Hz,1H),6.77(d,J＝8.3Hz,1H),6.45(s,1H),6.42–6.34 (m,2H),6.34–6.22(m,1H),6.19–6.07(m,1H),5.93(dd,J＝38.2,10.4Hz,1H),5.60–5.47 (m,1H),5.42(t,J＝9.3Hz,1H),5.27(s,1H),5.12(d,J＝28.7Hz,1H),4.76(d,J＝17.4Hz, 1H),4.26–4.16(m,1H),3.88(s,1H),3.85(d,J＝9.7Hz,3H),3.80(d,J＝4.8Hz,1H),3.76(d, J＝4.9Hz,1H),3.72–3.64(m,1H),3.59(d,J＝8.0Hz,1H),3.52(t,J＝14.4Hz,2H),3.41(s, 3H),3.37(s,2H),3.32(s,4H),3.13(d,J＝9.1Hz,3H),2.70(d,J＝10.7Hz,2H),2.58(dd,J＝ 16.3,5.5Hz,1H),2.34(s,1H),2.32(s,1H),2.17(d,J＝10.9Hz,1H),2.00(s,2H),1.93(s,1H), 1.83(d,J＝7.7Hz,2H),1.76(d,J＝5.6Hz,3H),1.73(s,1H),1.65(s,4H),1.61(d,J＝9.4Hz, 3H),1.52(d,J＝14.0Hz,1H),1.46(s,2H),1.41(d,J＝15.4Hz,1H),1.32(s,1H),1.30(d,J＝ 6.4Hz,1H),1.27(s,1H),1.20(d,J＝9.7Hz,1H),1.16(s,1H),1.14(s,1H),1.09(d,J＝5.6Hz, 3H),1.07–1.01(m,4H),0.99(d,J＝5.9Hz,3H),0.95(d,J＝6.2Hz,3H),0.90(d,J＝5.6Hz, 3H),0.72–0.61(m,1H).
13C NMR(126MHz,CDCl3)δ215.30,208.24,192.80,177.54,172.12,169.28,166.76,157.72, 139.99,136.93,136.01,133.53,132.35,130.20,130.13,129.46,129.38,128.69,128.37,126.94, 126.74,126.58,126.49,109.69,98.51,86.39,84.88,84.32,82.97,82.03,79.64,75.65,67.19, 59.24,56.57,55.86,52.76,51.28,46.57,44.21,41.46,40.72,40.22,38.95,38.12,35.20,35.08, 33.81,33.18,31.73,31.21,30.54,27.21,27.03,25.25,21.46,20.64,16.21,15.94,15.85,13.68, 13.24,10.18；
HRMS(ESI)m/z calcd for C68H91FN2NaO17,[M+Na]+1249.6199；Found:1249.6188.
实施例7：称取雷帕霉素(0.05mmol)、靛红3g(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-g，收率88％。
产物I-g结构式为：
I-g表征为:1H NMR(500MHz,CDCl3)δ8.14(s,1H),7.54(s,1H),7.25(d,J＝6.4Hz,1H), 7.21(d,J＝6.6Hz,2H),7.13(d,J＝6.9Hz,1H),7.07(s,1H),6.83–6.68(m,1H),6.48(d,J＝ 10.5Hz,1H),6.43–6.35(m,1H),6.35–6.27(m,2H),6.14(dd,J＝14.7,10.1Hz,1H),5.94 (dd,J＝39.6,10.5Hz,1H),5.60–5.46(m,1H),5.42(d,J＝10.1Hz,1H),5.27(s,1H),5.15(s, 1H),4.73(d,J＝28.2Hz,1H),4.26–4.15(m,1H),3.90(s,1H),3.86–3.79(m,3H),3.79– 3.75(m,1H),3.73–3.64(m,1H),3.60(d,J＝23.7Hz,1H),3.53(d,J＝20.8Hz,1H),3.40(d, J＝7.3Hz,3H),3.37(s,1H),3.35(s,1H),3.33(s,3H),3.13(d,J＝8.9Hz,3H),2.74–2.66(m, 2H),2.57(dd,J＝16.7,6.4Hz,1H),2.34(s,1H),2.32(s,1H),2.14(d,J＝12.1Hz,1H),2.05(d, J＝5.1Hz,4H),1.90(d,J＝13.9Hz,1H),1.88–1.84(m,1H),1.78(s,2H),1.76(s,2H),1.73 (s,2H),1.66(s,4H),1.61(d,J＝7.7Hz,3H),1.47(s,2H),1.45(s,1H),1.42(s,1H),1.30(d,J ＝5.7Hz,1H),1.26(s,2H),1.20(d,J＝9.5Hz,1H),1.16(s,1H),1.14(s,1H),1.08(d,J＝6.4 Hz,3H),1.07–1.01(m,4H),0.99(d,J＝5.9Hz,3H),0.95(d,J＝6.3Hz,3H),0.90(d,J＝5.8 Hz,3H),0.73–0.65(m,1H).
13C NMR(126MHz,CDCl3)δ215.22,208.25,192.88,177.92,172.04,169.30,166.75,162.55, 142.82,139.92,135.97,135.79,133.50,132.67,130.22,130.12,129.40,128.75,128.53,128.33, 127.04,126.74,126.53,123.44,108.35,108.17,98.52,86.36,84.86,84.29,82.93,81.27,77.78, 75.61,67.20,59.18,56.55,55.86,52.69,51.29,46.57,44.22,41.49,40.65,40.23,38.99,38.13, 35.24,35.06,33.84,33.19,31.67,31.20,30.69,27.20,27.03,25.25,21.44,20.64,16.20,15.91, 15.81,13.63,13.30,10.19；
HRMS(ESI)m/z calcd for C68H91FN2NaO17,[M+Na]+1249.6199；Found:1249.6163.
实施例8：称取雷帕霉素(0.05mmol)、靛红3h(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-h，收率82％。
产物I-h结构式为：
I-h表征为:1H NMR(500MHz,CDCl3)δ8.09(d,J＝48.2Hz,1H),7.55(s,1H),7.27–7.17(m, 2H),7.15(s,1H),6.94(s,1H),6.80(t,J＝11.2Hz,1H),6.58(d,J＝12.5Hz,1H),6.48(s,1H), 6.43–6.35(m,1H),6.35–6.26(m,1H),6.14(dd,J＝14.3,10.3Hz,1H),5.93(dd,J＝39.3, 10.2Hz,1H),5.61–5.47(m,1H),5.42(t,J＝10.8Hz,1H),5.27(s,1H),5.15(s,1H),4.77(s, 1H),4.26–4.16(m,1H),3.89(s,1H),3.82(d,J＝14.2Hz,4H),3.76(d,J＝5.3Hz,1H),3.72– 3.63(m,1H),3.56(d,J＝15.0Hz,2H),3.49(d,J＝14.3Hz,1H),3.40(s,3H),3.37(s,1H), 3.36(s,1H),3.32(s,3H),3.13(d,J＝8.7Hz,3H),2.69(d,J＝10.4Hz,2H),2.63–2.53(m, 1H),2.33(d,J＝11.2Hz,2H),2.15(d,J＝11.1Hz,1H),2.02(s,3H),1.92(s,1H),1.88–1.83 (m,1H),1.77(s,3H),1.75(s,2H),1.73(s,1H),1.66(m,4H),1.61(d,J＝7.3Hz,4H),1.47(s, 3H),1.43(s,1H),1.29(s,1H),1.26(s,3H),1.20(d,J＝10.1Hz,1H),1.16(s,1H),1.14(s,1H), 1.09(d,J＝6.1Hz,3H),1.07–1.01(m,4H),0.99(d,J＝5.5Hz,3H),0.95(d,J＝6.1Hz,3H), 0.90(d,J＝5.6Hz,3H),0.73–0.64(m,1H).
13C NMR(126MHz,CDCl3)δ215.27,208.23,177.54,171.97,169.28,166.76,142.40,140.03, 136.01,135.12,133.54,132.56,130.21,130.13,129.47,128.70,127.96,127.12,126.84,126.63, 126.48,126.40,121.98,109.88,98.51,86.39,84.86,84.33,82.94,81.25,77.76,75.64,67.19, 59.30,56.56,55.86,52.70,51.28,46.57,44.22,41.46,40.68,40.22,38.94,38.09,35.20,35.10, 33.81,33.16,31.70,31.22,30.70,27.21,27.03,25.26,21.48,20.63,16.22,15.93,15.84,13.69, 13.22,10.18；
HRMS(ESI)m/z calcd for C68H91ClN2NaO17,[M+Na]+1265.5903；Found:1265.5848.
实施例9：称取雷帕霉素(0.05mmol)、靛红3i(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-i，收率80％。
产物I-i结构式为：
I-i表征为:1H NMR(500MHz,CDCl3)δ8.05(s,1H),7.56(s,1H),7.46(d,J＝6.4Hz,1H), 7.35(d,J＝7.2Hz,1H),7.23(m,1H),7.15(s,1H),7.09(d,J＝3.6Hz,1H),6.80(d,J＝8.7Hz, 1H),6.56(s,1H),6.45–6.35(m,1H),6.35–6.26(m,1H),6.15(dd,J＝14.7,10.1Hz,1H), 5.94(dd,J＝37.6,10.5Hz,1H),5.61–5.47(m,1H),5.43(t,J＝11.4Hz,1H),5.28(s,1H), 5.16(s,1H),4.78(s,1H),4.25–4.15(m,1H),3.88(s,1H),3.84(d,J＝12.7Hz,3H),3.76(d,J ＝5.8Hz,1H),3.71(d,J＝5.8Hz,1H),3.67(t,J＝7.2Hz,1H),3.59(s,1H),3.56(s,1H),3.51 (d,J＝15.2Hz,1H),3.41(s,3H),3.39(s,1H),3.38(s,1H),3.34(s,3H),3.14(d,J＝9.4Hz, 3H),2.71(d,J＝10.3Hz,2H),2.59(dd,J＝16.6,5.8Hz,1H),2.34(s,1H),2.32(s,1H),2.17(d, J＝12.4Hz,1H),1.99(dd,J＝16.2,6.4Hz,1H),1.93(s,1H),1.90–1.86(m,2H),1.84(d,J＝ 8.3Hz,1H),1.78(s,3H),1.76(s,3H),1.73(s,1H),1.66(s,4H),1.61(d,J＝8.4Hz,3H),1.50 (d,J＝11.8Hz,2H),1.47(s,2H),1.43(d,J＝8.3Hz,1H),1.34(s,1H),1.30(s,1H),1.28(s, 1H),1.21(d,J＝11.6Hz,2H),1.16(s,1H),1.15(s,1H),1.10(d,J＝6.4Hz,3H),1.08–1.02 (m,4H),1.00(d,J＝6.1Hz,3H),0.96(d,J＝6.3Hz,3H),0.91(d,J＝6.2Hz,3H),0.71(dd,J＝ 24.9,12.5Hz,1H).
13C NMR(126MHz,CDCl3)δ215.53,208.22,177.16,171.89,169.29,166.77,141.77,140.08, 136.02,133.57,132.28,130.21,130.16,129.51,128.50,127.20,126.95,126.68,126.47,124.78, 122.62,119.04,105.97,98.51,86.41,84.84,84.35,82.94,81.22,77.77,75.62,67.20,59.35, 56.51,55.87,52.75,51.28,46.57,44.22,41.45,40.64,40.21,38.93,38.09,35.15,35.10,33.79, 33.11,31.68,31.23,30.70,27.24,27.03,25.26,21.50,20.63,16.22,15.93,15.84,13.74,13.17, 10.17；
HRMS(ESI)m/z calcd for C69H91F3N2NaO17,[M+Na]+1299.6167；Found:1299.6199.
实施例10：称取雷帕霉素(0.05mmol)、靛红3j(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-j，收率85％。
产物I-j结构式为：
I-j表征为:1H NMR(500MHz,CDCl3)δ7.67(s,1H),7.56(s,1H),7.26(d,J＝6.6Hz,1H), 7.20(t,J＝12.9Hz,2H),7.16–7.07(m,1H),6.90–6.83(m,2H),6.78(d,J＝3.4Hz,1H), 6.50(d,J＝12.1Hz,1H),6.46–6.35(m,1H),6.35–6.26(m,1H),6.14(dd,J＝14.6,10.2Hz, 1H),5.93(dd,J＝37.5,10.3Hz,1H),5.59–5.47(m,1H),5.43(t,J＝11.2Hz,1H),5.28(s,1H), 5.16(s,1H),4.76(d,J＝27.2Hz,1H),4.24–4.15(m,1H),3.86(s,1H),3.83(s,3H),3.79(d,J ＝11.8Hz,1H),3.74(d,J＝5.4Hz,1H),3.73–3.68(m,1H),3.66(d,J＝7.3Hz,1H),3.57(d,J ＝11.7Hz,1H),3.51(d,J＝15.2Hz,2H),3.41(d,J＝13.2Hz,4H),3.36(s,1H),3.33(s,3H), 3.14(d,J＝8.1Hz,3H),2.73(d,J＝4.5Hz,1H),2.69(d,J＝4.9Hz,1H),2.58(dd,J＝16.8, 6.1Hz,1H),2.34(s,1H),2.32(s,1H),2.15(d,J＝11.9Hz,1H),2.03–1.96(m,1H),1.89(s, 2H),1.85(s,1H),1.78(d,J＝11.6Hz,3H),1.76(s,3H),1.73(s,1H),1.66(s,4H),1.61(d,J＝ 9.1Hz,4H),1.53(d,J＝11.4Hz,1H),1.47(s,2H),1.43(d,J＝7.9Hz,1H),1.34(s,1H),1.30 (d,J＝6.6Hz,1H),1.27(s,1H),1.20(d,J＝12.5Hz,1H),1.16(s,1H),1.15(s,1H),1.10(d,J ＝6.1Hz,3H),1.08–1.02(m,4H),1.00(d,J＝6.1Hz,3H),0.95(d,J＝6.3Hz,3H),0.91(d,J ＝5.7Hz,3H),0.71(dd,J＝21.8,10.1Hz,1H).
13C NMR(101MHz,CDCl3)δ215.68,208.26,192.70,176.61,171.91,169.29,166.77,145.23, 140.10,136.03,135.64,133.58,132.53,130.41,130.20,130.11,129.53,128.73,128.63,127.06, 126.77,126.68,126.45,98.49,85.79,84.82,84.36,82.97,81.74,77.78,75.63,67.18,59.37, 56.61,55.87,52.73,51.27,46.57,44.22,41.45,40.65,40.20,38.89,38.08,35.24,35.14,33.77, 33.11,32.60,31.71,31.23,30.72,27.23,27.04,25.27,21.51,20.62,16.24,15.94,15.88,13.73, 13.16,10.17；
HRMS(ESI)m/z calcd for C68H91FN2NaO17,[M+Na]+1249.6199；Found:1249.6173.
实施例11：称取雷帕霉素(0.05mmol)、靛红3k(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-k，收率79％。
产物I-k结构式为：
I-k表征为:1H NMR(500MHz,CDCl3)δ7.68(d,J＝30.6Hz,1H),7.55(s,1H),7.21(d,J＝6.6Hz,2H),7.14(d,J＝6.9Hz,1H),7.07(d,J＝7.9Hz,1H),6.94(s,1H),6.82–6.70(m,1H), 6.51(s,1H),6.43–6.34(m,1H),6.34–6.22(m,1H),6.19–6.06(m,1H),5.94(dt,J＝18.7, 8.7Hz,1H),5.52(dt,J＝21.6,9.7Hz,1H),5.42(t,J＝11.1Hz,1H),5.27(s,1H),5.15(s,1H), 4.78(s,1H),4.20(dd,J＝23.7,10.5Hz,1H),3.85(s,1H),3.81(d,J＝12.1Hz,3H),3.74(d,J ＝5.0Hz,1H),3.67(dd,J＝16.2,9.0Hz,1H),3.57(d,J＝13.2Hz,1H),3.50(d,J＝14.7Hz, 1H),3.39(s,3H),3.38(s,1H),3.36(s,1H),3.33(s,3H),3.13(d,J＝7.6Hz,3H),2.72(s,1H), 2.69(s,1H),2.58(dd,J＝16.6,5.9Hz,1H),2.34(s,1H),2.32(s,1H),2.16(s,1H),2.14(s,1H), 2.02(d,J＝6.6Hz,1H),2.00–1.97(m,1H),1.93(s,1H),1.85(d,J＝6.6Hz,1H),1.76(d,J＝ 7.7Hz,4H),1.73(s,1H),1.66(s,4H),1.61(d,J＝8.2Hz,3H),1.52(d,J＝10.0Hz,1H),1.48 (d,J＝10.7Hz,2H),1.43(s,1H),1.34(s,1H),1.29(s,2H),1.21(s,1H),1.16(s,1H),1.15(s, 1H),1.09(d,J＝6.0Hz,3H),1.04(dd,J＝13.6,6.1Hz,5H),0.99(d,J＝5.9Hz,3H),0.95(d,J ＝6.1Hz,3H),0.90(d,J＝4.6Hz,4H),0.74–0.65(m,1H)；
13C NMR(101MHz,CDCl3)δ215.47,208.25,192.70,176.44,171.87,169.29,166.76,140.09, 138.84,136.03,135.96,133.57,132.41,130.20,130.10,129.52,129.30,128.66,128.38,127.09, 126.81,126.68,126.46,122.88,114.24,98.49,85.83,84.80,84.35,82.96,82.42,77.76,75.62, 67.19,59.38,56.60,55.88,52.72,51.27,46.56,44.22,41.46,40.63,40.19,38.91,38.08,35.15, 33.78,33.10,31.70,31.23,30.71,27.23,27.04,25.27,21.51,20.63,16.24,15.94,15.87,13.74, 13.16,10.18；
HRMS(ESI)m/z calcd for C68H91ClN2NaO17,[M+Na]+1265.5903；Found:1265.5882.
实施例12：称取雷帕霉素(0.05mmol)、靛红3l(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-l，收率86％。
产物I-l结构式为：
I-l表征为:1HNMR(500MHz,CDCl3)δ7.44(s,1H),7.38(s,1H),7.12(s,2H),7.08(d,J＝7.3 Hz,2H),6.91(t,J＝7.3Hz,1H),6.38(dd,J＝15.2,10.3Hz,2H),6.32(d,J＝10.4Hz,1H), 6.24(s,1H),6.14(dd,J＝14.4,10.5Hz,1H),6.01–5.86(m,1H),5.59–5.46(m,1H),5.41(d, J＝10.0Hz,1H),5.27(d,J＝3.9Hz,1H),5.16(s,1H),4.77(d,J＝23.4Hz,1H),4.22–4.10 (m,1H),3.86(d,J＝9.4Hz,3H),3.82–3.76(m,1H),3.73(d,J＝5.8Hz,1H),3.66(t,J＝7.2 Hz,1H),3.60(d,J＝17.7Hz,1H),3.56(s,1H),3.47(s,1H),3.45–3.40(m,1H),3.40–3.35 (m,3H),3.33(s,4H),3.13(d,J＝8.2Hz,3H),2.85(d,J＝14.5Hz,3H),2.73(s,1H),2.70(d,J ＝5.2Hz,1H),2.62–2.50(m,1H),2.34(s,1H),2.32(s,1H),2.14(d,J＝12.0Hz,1H),1.95(s, 3H),1.85(dd,J＝18.4,11.9Hz,1H),1.78(s,1H),1.76(d,J＝7.2Hz,4H),1.73(s,1H),1.66(s, 4H),1.60(d,J＝10.3Hz,3H),1.49(s,1H),1.47(s,1H),1.45(s,1H),1.42(d,J＝13.0Hz,1H), 1.32(s,3H),1.20(d,J＝13.6Hz,1H),1.16(s,1H),1.14(s,1H),1.09(d,J＝6.4Hz,3H),1.04 (dd,J＝12.1,6.1Hz,4H),0.99(d,J＝6.1Hz,3H),0.95(d,J＝6.4Hz,2H),0.91(d,J＝6.4Hz, 3H),0.73–0.61(m,1H).
13C NMR(126MHz,CDCl3)δ215.50,208.22,192.64,175.57,172.10,169.28,166.77,143.56, 140.14,136.07,135.59,133.60,133.02,130.18,129.82,129.54,129.45,128.68,127.92,127.05, 126.78,126.69,126.42,126.32,122.14,107.29,98.49,85.32,84.84,84.34,83.05,81.94,77.86, 75.65,67.18,59.37,56.70,55.86,52.64,51.28,46.55,44.21,41.43,40.70,40.19,38.89,38.12, 35.39,35.16,33.77,33.15,31.78,31.24,30.56,27.24,27.04,25.58,25.26,21.53,20.62,16.23, 15.97,15.93,13.77,13.12,10.16；
HRMS(ESI)m/z calcd for C69H94N2NaO17,[M+Na]+1245.6449；Found:1245.6418.
实施例13：称取雷帕霉素(0.05mmol)、靛红3m(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-m，收率86％。
产物I-m结构式为：
I-m表征为:1H NMR(500MHz,CDCl3)δ7.93(d,J＝29.3Hz,1H),7.51(s,1H),7.23(d,J＝ 6.8Hz,1H),7.18(d,J＝7.1Hz,2H),7.11(s,1H),6.98–6.81(m,2H),6.50(s,1H),6.43–6.34 (m,1H),6.34–6.26(m,1H),6.13(dd,J＝14.5,10.5Hz,1H),6.00–5.85(m,1H),5.52(dt,J＝ 20.6,9.4Hz,1H),5.41(t,J＝10.4Hz,1H),5.27(s,1H),5.14(d,J＝4.4Hz,1H),4.75(d,J＝ 21.8Hz,1H),4.19(dd,J＝17.3,5.2Hz,1H),3.88(d,J＝23.1Hz,2H),3.81(d,J＝11.9Hz, 3H),3.74(d,J＝5.9Hz,1H),3.67(dd,J＝16.5,9.2Hz,1H),3.60–3.53(m,1H),3.50(d,J＝ 14.6Hz,1H),3.41(d,J＝22.2Hz,3H),3.37(s,1H),3.36(s,1H),3.33(s,3H),3.12(d,J＝7.9 Hz,3H),2.72(d,J＝5.2Hz,1H),2.68(d,J＝5.1Hz,1H),2.58(dd,J＝16.7,6.2Hz,1H),2.33 (s,1H),2.31(s,1H),2.16(s,1H),2.14(s,1H),2.02–1.97(m,1H),1.93(s,1H),1.83(d,J＝8.4 Hz,1H),1.76(d,J＝7.5Hz,5H),1.72(s,1H),1.65(s,4H),1.60(d,J＝9.1Hz,3H),1.48(s, 1H),1.46(s,2H),1.44(s,1H),1.32(d,J＝6.0Hz,1H),1.29(s,1H),1.26(s,1H),1.19(d,J＝ 13.2Hz,1H),1.15(s,1H),1.14(s,1H),1.09(d,J＝6.3Hz,3H),1.04(dd,J＝13.7,6.8Hz,4H), 0.99(d,J＝6.2Hz,3H),0.94(d,J＝6.4Hz,3H),0.90(d,J＝5.5Hz,3H),0.67(dd,J＝23.8, 11.8Hz,1H).
13C NMR(101MHz,CDCl3)δ215.44,208.24,176.89,171.78,170.47,169.30,166.76,140.08, 138.63,136.02,135.95,133.56,132.16,130.21,130.04,129.44,128.57,128.41,127.06,126.83, 126.66,126.46,126.05,124.96,122.26,121.81,111.22,98.49,85.71,84.77,84.33,82.94,80.63, 77.76,75.60,67.19,59.36,56.52,55.86,52.72,51.27,46.56,44.22,41.47,40.61,40.18,38.91, 38.08,35.15,35.08,33.78,33.09,31.68,31.22,30.64,27.22,27.03,25.25,21.50,20.62,16.22, 15.92,15.86,13.72,13.15,10.17；
HRMS(ESI)m/z calcd for C69H91F3N2NaO17,[M+Na]+1299.6167；Found:1299.6126.
实施例14：称取雷帕霉素(0.05mmol)、靛红3n(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-n，收率90％。
产物I-n结构式为：
I-n表征为:1H NMR(500MHz,CDCl3)δ8.27(d,J＝30.9Hz,1H),7.53(s,1H),7.25–7.18 (m,2H),7.15(s,1H),6.41(s,2H),6.37(d,J＝11.3Hz,1H),6.34–6.24(m,1H),6.19–6.06 (m,1H),5.93(dd,J＝40.0,10.2Hz,1H),5.51(dd,J＝24.8,10.1Hz,1H),5.41(d,J＝9.8Hz, 1H),5.27(s,1H),5.14(s,1H),4.74(d,J＝23.2Hz,1H),4.20(dd,J＝14.3,5.3Hz,1H),3.87(s, 1H),3.83(s,1H),3.82(s,3H),3.78(d,J＝5.1Hz,1H),3.70(d,J＝5.8Hz,1H),3.66(t,J＝7.3 Hz,1H),3.60–3.53(m,1H),3.48(d,J＝13.7Hz,1H),3.41(s,3H),3.36(s,2H),3.31(s,3H), 3.12(d,J＝9.2Hz,3H),2.69(s,1H),2.67(s,1H),2.63–2.52(m,1H),2.33(s,1H),2.31(s, 1H),2.18(s,1H),2.16(s,1H),2.00(s,1H),1.92(s,1H),1.88–1.83(m,1H),1.78(s,1H),1.76 (d,J＝7.1Hz,3H),1.72(d,J＝4.8Hz,1H),1.65(s,4H),1.60(d,J＝8.9Hz,3H),1.46(s,2H), 1.44(s,1H),1.42(s,1H),1.29(d,J＝6.4Hz,1H),1.26(s,2H),1.22–1.18(m,1H),1.15(s, 1H),1.14(s,1H),1.08(d,J＝6.3Hz,3H),1.03(d,J＝4.8Hz,4H),0.98(d,J＝5.7Hz,3H), 0.94(d,J＝6.2Hz,3H),0.90(d,J＝5.7Hz,3H),0.67(dd,J＝23.3,11.4Hz,1H).
13C NMR(101MHz,CDCl3)δ215.16,208.25,192.94,177.68,172.11,169.29,166.75,149.81, 139.87,137.56,135.96,133.47,132.18,130.23,130.08,129.38,128.52,127.12,126.91,126.53, 123.40,116.96,98.51,86.35,84.84,84.29,82.93,81.64,77.72,75.63,67.20,59.13,56.47, 55.86,52.81,51.27,46.58,44.22,41.49,40.70,40.22,38.98,38.11,35.09,35.03,33.84,33.20, 31.70,31.18,30.52,27.19,27.04,25.24,21.42,20.64,16.20,15.91,15.78,13.59,13.32,10.19； HRMS(ESI)m/zcalcd for C68H90F2N2NaO17,[M+Na]+1267.6105；Found:1267.6079.
实施例15：称取雷帕霉素(0.05mmol)、靛红3o(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-o1，I-o2收率87％。
产物I-o1结构式为：
I-o1表征为:1H NMR(500MHz,CDCl3)δ7.51(s,2H),7.36(d,J＝5.7Hz,1H),7.24(dd,J＝ 14.3,7.0Hz,2H),7.17(d,J＝5.5Hz,1H),7.09(d,J＝5.7Hz,4H),7.03(t,J＝7.9Hz,2H), 6.88(t,J＝6.8Hz,1H),6.40(d,J＝13.1Hz,1H),6.36(d,J＝4.7Hz,1H),6.33(d,J＝11.4Hz, 1H),6.15(dd,J＝15.0,10.1Hz,1H),5.94(dd,J＝35.6,10.7Hz,1H),5.54(dd,J＝15.1,9.0Hz, 1H),5.42(d,J＝9.6Hz,1H),5.28(d,J＝5.1Hz,1H),5.16(d,J＝4.4Hz,1H),4.78(d,J＝25.8 Hz,1H),4.64(d,J＝15.6Hz,1H),4.60(s,1H),4.19(dd,J＝15.0,5.8Hz,1H),3.88(d,J＝7.1 Hz,1H),3.80(m,4H),3.73(d,J＝6.1Hz,1H),3.70–3.64(m,1H),3.59(s,1H),3.55(d,J＝ 13.8Hz,1H),3.47(s,1H),3.40(s,3H),3.39(s,1H),3.37(s,1H),3.34(s,3H),3.14(d,J＝7.9 Hz,3H),2.74(d,J＝5.7Hz,1H),2.71(d,J＝5.8Hz,1H),2.59(dd,J＝16.9,6.1Hz,1H),2.35 (s,1H),2.33(s,1H),2.17(m,1H),2.01(d,J＝6.0Hz,1H),2.00–1.96(m,1H),1.93(s,1H), 1.87(m,2H),1.76(d,J＝5.8Hz,4H),1.73(s,1H),1.66(s,4H),1.61(d,J＝9.3Hz,3H),1.48 (s,2H),1.46(s,1H),1.44(s,1H),1.34(s,1H),1.30(s,1H),1.28(s,1H),1.27(s,1H),1.20(d,J ＝10.7Hz,1H),1.17(s,1H),1.15(s,1H),1.10(s,3H),1.05(dd,J＝14.6,6.7Hz,4H),1.00(d,J ＝6.4Hz,3H),0.96(d,J＝6.5Hz,3H),0.92(d,J＝6.6Hz,3H),0.70(dd,J＝23.4,11.6Hz, 1H)；
13C NMR(126MHz,CDCl3)δ215.60,208.22,192.58,175.80,172.16,169.28,166.78,140.17, 136.07,135.34,133.62,133.01,130.18,130.13,129.58,129.45,129.05,128.56,128.52,127.40, 127.29,127.14,126.95,126.73,126.57,126.41,122.21,108.55,98.49,86.38,84.83,84.36, 83.03,81.66,77.82,77.04,75.67,67.18,59.43,56.70,55.87,52.62,51.28,46.56,44.21,43.67, 41.43,40.71,40.19,38.88,38.09,35.36,35.19,33.76,33.13,31.79,31.25,30.60,27.25,27.05, 25.28,21.54,20.62,16.24,15.97,15.94,13.79,13.09,10.17；
HRMS(ESI)m/z calcd for C75H98N2NaO17,[M+Na]+1321.6762；Found:1321.6796.
产物I-o2结构式为：
I-o2表征为:1H NMR(500MHz,CDCl3)δ7.51(d,J＝14.8Hz,1H),7.36(m,1H),7.22(s, 2H),7.17(d,J＝6.4Hz,2H),7.10(m,2H),7.05(m,2H),7.01(d,J＝8.9Hz,2H),6.87(m,1H), 6.41(d,J＝14.4Hz,1H),6.36(d,J＝14.1Hz,1H),6.31(d,J＝8.6Hz,1H),6.15(dd,J＝15.0, 10.3Hz,1H),5.95(dd,J＝38.4,10.7Hz,1H),5.59–5.48(m,1H),5.44(d,J＝9.7Hz,1H), 5.29(d,J＝5.1Hz,1H),5.18(d,J＝4.7Hz,1H),4.79(d,J＝26.4Hz,1H),4.62(q,J＝15.7Hz, 2H),4.21(d,J＝5.4Hz,1H),3.88(d,J＝7.3Hz,3H),3.81(s,1H),3.77(d,J＝5.5Hz,1H), 3.75–3.70(m,1H),3.67(t,J＝7.4Hz,1H),3.60–3.52(m,3H),3.44(s,1H),3.41(s,1H), 3.37(s,1H),3.35(s,1H),3.34(s,3H),3.19–3.11(m,3H),2.72(d,J＝5.8Hz,1H),2.59(dd,J ＝16.7,6.2Hz,1H),2.36(s,1H),2.33(s,1H),2.15(d,J＝11.5Hz,1H),2.01(d,J＝7.3Hz,1H), 1.99(d,J＝7.2Hz,1H),1.94(d,J＝6.8Hz,1H),1.88–1.84(m,1H),1.79(s,2H),1.76(d,J＝ 5.7Hz,3H),1.74(s,1H),1.67(s,3H),1.61(dd,J＝18.1,9.0Hz,4H),1.48(s,2H),1.46(s,1H), 1.44(s,1H),1.35(s,1H),1.32(d,J＝6.7Hz,1H),1.30(s,1H),1.29(s,1H),1.20(d,J＝11.2 Hz,1H),1.17(s,1H),1.16(s,1H),1.11(d,J＝6.6Hz,3H),1.07(s,1H),1.05(d,J＝6.8Hz, 3H),1.00(d,J＝6.3Hz,3H),0.96(d,J＝6.5Hz,3H),0.92(d,J＝6.7Hz,3H),0.74–0.62(m, 1H).
13C NMR(126MHz,CDCl3)δ215.24,208.22,192.77,175.83,170.67,169.28,166.74,140.11, 135.99,135.35,133.59,133.03,130.18,130.14,129.49,129.40,129.05,128.53,128.04,127.94, 127.40,127.29,127.15,126.73,126.57,126.45,122.21,108.66,98.50,87.04,84.81,84.31, 83.74,81.98,79.60,77.04,75.48,67.20,59.27,57.67,55.88,52.40,51.29,46.58,44.22,43.69, 41.50,40.55,40.21,38.97,38.26,36.04,35.13,33.81,33.20,32.08,31.73,31.24,29.70,27.24, 27.04,25.28,21.48,20.66,16.24,16.00,15.83,13.73,13.26,10.18；
HRMS(ESI)m/z calcd for C75H98N2NaO17,[M+Na]+1321.6762；Found:1321.6797.
实施例16：称取雷帕霉素(0.05mmol)、靛红3p(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮 2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-p1，收率74％。
产物I-p1结构式为：
I-p1表征为:1HNMR(500MHz,CDCl3)δ7.88(s,1H),7.56(s,2H),7.48(d,J＝13.6Hz,1H), 7.42–7.32(m,1H),7.21(d,J＝6.2Hz,1H),7.17(d,J＝6.6Hz,2H),7.06–6.92(m,1H),6.89 (d,J＝7.5Hz,1H),6.75(t,J＝7.0Hz,1H),6.43–6.35(m,1H),6.35–6.27(m,1H),6.14(dd, J＝14.7,10.0Hz,1H),5.94(dd,J＝37.4,10.6Hz,1H),5.60–5.46(m,1H),5.43(t,J＝12.0 Hz,1H),5.28(s,1H),5.16(d,J＝4.3Hz,1H),4.80(s,1H),4.23–4.16(m,1H),3.92–3.84(m, 1H),3.80(d,J＝18.4Hz,3H),3.74(d,J＝5.1Hz,1H),3.71(d,J＝6.0Hz,1H),3.69–3.64(m, 1H),3.58(s,1H),3.55(d,J＝10.8Hz,1H),3.48(s,1H),3.44–3.39(m,3H),3.35(s,2H),3.34 (s,3H),3.14(d,J＝8.5Hz,3H),2.73(s,1H),2.70(d,J＝4.9Hz,1H),2.59(dd,J＝16.7,5.9Hz, 1H),2.38–2.27(m,2H),2.15(d,J＝12.8Hz,1H),2.05(s,1H),2.01(s,3H),1.97(s,1H),1.92 (s,1H),1.87(s,1H),1.85(d,J＝6.5Hz,1H),1.79(s,1H),1.76(s,3H),1.73(s,1H),1.66(s, 3H),1.61(d,J＝9.9Hz,4H),1.52(s,1H),1.48(d,J＝11.4Hz,2H),1.45(s,1H),1.34(s,1H), 1.30(s,1H),1.28(s,1H),1.19(s,1H),1.16(s,1H),1.15(s,1H),1.10(d,J＝6.4Hz,3H),1.05 (dd,J＝13.6,5.9Hz,4H),1.00(d,J＝6.1Hz,3H),0.96(d,J＝6.3Hz,3H),0.91(d,J＝6.4Hz, 3H),0.69(dd,J＝23.5,11.7Hz,1H).
13C NMR(126MHz,CDCl3)δ215.47,208.25,192.80,177.86,172.02,169.28,166.77,140.11, 139.61,136.05,135.62,133.59,132.87,130.75,130.14,129.54,128.27,127.33,126.78,126.67, 126.44,121.98,118.09,98.50,85.81,84.89,84.35,83.01,82.08,77.73,75.66,67.19,59.34, 56.68,55.86,52.55,51.28,46.56,44.21,41.43,40.70,40.20,38.90,38.11,35.32,35.13,33.78, 33.16,31.74,31.24,30.68,27.24,27.04,25.27,21.51,20.63,16.23,15.96,15.92,15.90,13.75, 13.16,10.30,10.17；
HRMS(ESI)m/z calcd for C69H94N2NaO17,[M+Na]+1245.6449；Found:1245.6417.
实施例17：称取雷帕霉素(0.05mmol)、靛红3q(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物I-q，收率89％。
产物I-q结构式为：
I-q表征为:1H NMR(400MHz,CDCl3)δ7.92(t,J＝8.0Hz,1H),7.47(d,J＝6.8Hz,1H), 7.24(d,J＝7.4Hz,1H),7.22–7.15(m,2H),7.12(t,J＝7.6Hz,1H),7.05(s,1H),7.03–6.95 (m,1H),6.54(d,J＝8.5Hz,1H),6.45–6.34(m,1H),6.34–6.25(m,1H),6.14(dd,J＝14.9, 10.1Hz,1H),5.93(dd,J＝28.7,10.6Hz,1H),5.60–5.46(m,1H),5.41(d,J＝9.9Hz,1H), 5.27(s,1H),5.21–5.10(m,1H),4.78(t,J＝12.0Hz,1H),4.23–4.14(m,1H),3.87(d,J＝4.1 Hz,1H),3.84(s,1H),3.82–3.77(m,3H),3.77–3.72(m,1H),3.72–3.67(m,1H),3.65(d,J＝ 7.5Hz,1H),3.57(d,J＝13.9Hz,1H),3.49(s,1H),3.47(d,J＝3.3Hz,1H),3.41(s,3H),3.38 (d,J＝2.0Hz,1H),3.37(s,1H),3.33(s,3H),3.13(d,J＝7.6Hz,3H),2.73(d,J＝5.6Hz,1H), 2.69(d,J＝5.6Hz,1H),2.65–2.54(m,3H),2.52(s,1H),2.35(d,J＝5.4Hz,1H),2.31(s,1H), 2.19(d,J＝10.9Hz,1H),2.13(d,J＝14.3Hz,1H),2.05(s,1H),2.00(s,1H),1.98(d,J＝5.0 Hz,1H),1.95(d,J＝6.4Hz,1H),1.88(d,J＝7.3Hz,1H),1.85(d,J＝7.6Hz,1H),1.75(d,J＝ 4.1Hz,4H),1.73(s,1H),1.66(s,4H),1.62(s,1H),1.60(s,2H),1.50(s,1H),1.47(s,2H),1.43 (s,1H),1.34(s,1H),1.29(s,1H),1.28(s,1H),1.19(d,J＝2.5Hz,1H),1.16(s,1H),1.14(s, 1H),1.09(d,J＝6.6Hz,3H),1.06(d,J＝6.8Hz,1H),1.03(d,J＝6.6Hz,3H),0.99(d,J＝6.4 Hz,3H),0.95(d,J＝6.5Hz,3H),0.93–0.89(m,4H),0.71(dd,J＝21.8,9.3Hz,1H)；
13C NMR(126MHz,CDCl3)δ215.34,208.22,192.82,177.06,171.85,170.14,169.29,166.76, 140.50,140.10,136.05,135.44,133.57,132.17,130.21,130.04,129.94,128.92,127.07,126.73, 126.49,126.45,126.24,124.44,115.58,98.49,86.62,84.79,84.33,82.88,81.20,77.85,75.58, 67.19,59.38,56.48,55.86,52.67,51.28,46.54,44.21,41.46,40.59,40.18,38.94,38.09,35.91, 35.18,33.79,33.15,31.22,31.02,30.63,27.23,27.02,26.49,25.25,21.52,20.62,16.22,15.92, 15.85,13.15,10.31,10.17；
HRMS(ESI)m/z calcd for C70H94N2NaO18,[M+Na]+1273.6399；Found:1273.6386.
实施例18：称取雷帕霉素(0.05mmol)、靛红3r(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-r1，I-r2，收率74％,， dr＝60:40。
产物I-r1结构式为：
I-r1表征为:1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.8Hz,2H),7.28–7.21(m,4H),7.19 (d,J＝7.1Hz,1H),7.11(t,J＝7.2Hz,2H),7.03(d,J＝4.7Hz,2H),6.74(td,J＝8.8,2.6Hz, 1H),6.44(d,J＝7.8Hz,1H),6.42–6.36(m,1H),6.36–6.27(m,1H),6.22(dd,J＝8.3,4.1Hz, 1H),6.15(dd,J＝15.0,10.0Hz,1H),5.94(dd,J＝26.3,10.3Hz,1H),5.54(dd,J＝15.1,8.8Hz, 1H),5.42(d,J＝10.0Hz,1H),5.29(d,J＝4.9Hz,1H),5.13(ddd,J＝32.1,10.7,5.5Hz,1H), 4.84(s,1H),4.63(d,J＝15.8Hz,1H),4.54(d,J＝15.8Hz,1H),4.19(dd,J＝13.2,6.3Hz,1H), 3.86(s,3H),3.72(d,J＝6.1Hz,1H),3.67(t,J＝7.4Hz,1H),3.59(d,J＝12.5Hz,1H),3.45(s, 3H),3.40(s,2H),3.35(s,3H),3.14(d,J＝6.9Hz,3H),2.76(d,J＝5.8Hz,1H),2.72(d,J＝5.9 Hz,1H),2.60(dd,J＝16.9,6.3Hz,1H),2.36(s,1H),2.33(s,1H),2.20(d,J＝11.3Hz,1H), 2.00(d,J＝5.3Hz,1H),1.97(d,J＝6.4Hz,1H),1.91–1.87(m,1H),1.85(dd,J＝6.7,2.4Hz, 1H),1.82(s,1H),1.77(t,J＝5.1Hz,4H),1.74(s,1H),1.67(s,4H),1.64–1.58(m,3H),1.50 (d,J＝4.8Hz,1H),1.48–1.43(m,2H),1.42(d,J＝5.5Hz,1H),1.34(d,J＝5.8Hz,1H), 1.33–1.30(m,1H),1.28(s,1H),1.21(dd,J＝7.1,3.3Hz,1H),1.17(s,1H),1.16(d,J＝3.0Hz, 1H),1.11(d,J＝6.8Hz,3H),1.06(dd,J＝13.8,6.6Hz,4H),1.01(d,J＝6.5Hz,3H),0.96(d,J ＝6.6Hz,3H),0.93(d,J＝6.7Hz,3H),0.75–0.64(m,1H).
13C NMR(101MHz,CDCl3)δ215.75,208.23,192.51,175.55,172.31,169.29,166.77,140.18, 138.93,136.06,135.55,134.93,133.63,132.42,130.19,129.61,128.63,128.14,127.55,127.29, 126.87,126.42,115.79,115.55,109.07,108.98,98.47,86.35,84.71,84.37,83.02,81.81,77.74, 75.69,67.16,59.50,56.63,55.90,52.83,51.25,46.58,44.22,43.76,41.45,40.73,40.17,38.86, 38.04,35.21,33.73,33.07,31.83,31.26,30.40,27.25,27.07,25.29,21.56,20.63,16.28,15.96, 13.77,13.06,10.18；
HRMS(ESI)m/z calcd for C75H97FN2NaO17,[M+Na]+1339.6668；Found:1339.6643.
产物I-r2结构式为：
I-r2表征为:1H NMR(500MHz,CDCl3)δ7.24(dd,J＝5.0,1.6Hz,4H),7.19(d,J＝10.5Hz, 2H),7.10(t,J＝7.4Hz,2H),7.00(d,J＝11.5Hz,2H),6.93(s,1H),6.73(td,J＝8.8,2.7Hz, 1H),6.40(dd,J＝14.7,10.6Hz,1H),6.32(dd,J＝14.8,10.2Hz,1H),6.22(dd,J＝8.4,4.1Hz, 1H),6.15(ddd,J＝15.6,10.3,5.4Hz,1H),5.95(dd,J＝34.8,10.5Hz,1H),5.59–5.50(m,1H), 5.44(t,J＝8.4Hz,1H),5.33–5.26(m,1H),5.16(dt,J＝17.9,6.1Hz,1H),4.79(s,1H),4.64(d, J＝16.4Hz,1H),4.61–4.55(m,1H),4.22(dd,J＝19.2,5.8Hz,1H),3.89(d,J＝7.3Hz,3H), 3.75(d,J＝5.8Hz,1H),3.67(t,J＝7.6Hz,1H),3.54(d,J＝15.0Hz,3H),3.44(s,1H),3.35(s, 1H),3.34(s,3H),3.17–3.12(m,3H),2.78–2.73(m,1H),2.72(d,J＝5.7Hz,1H),2.60(dd,J ＝16.8,6.4Hz,1H),2.37(s,1H),2.34(s,1H),2.18(d,J＝10.0Hz,1H),2.05(dd,J＝12.1,8.2 Hz,1H),2.00(dd,J＝11.3,5.9Hz,2H),1.90–1.85(m,1H),1.80(d,J＝5.5Hz,1H),1.77(s, 3H),1.75(s,1H),1.69(s,1H),1.67(s,4H),1.62(dd,J＝10.4,5.1Hz,3H),1.52(d,J＝5.4Hz, 1H),1.49–1.45(m,2H),1.44(d,J＝7.2Hz,1H),1.32(s,1H),1.31(d,J＝3.7Hz,1H),1.28(s, 1H),1.21(s,1H),1.18(s,1H),1.17(d,J＝6.8Hz,1H),1.12(d,J＝6.8Hz,3H),1.05(q,J＝8.1 Hz,4H),1.00(d,J＝6.5Hz,3H),0.97(d,J＝6.6Hz,3H),0.93(d,J＝6.8Hz,3H),0.80(d,J＝ 11.9Hz,1H)；
13C NMR(101MHz,CDCl3)δ215.47,208.24,175.72,170.56,169.28,166.74,140.18,139.00, 136.00,135.04,133.63,130.19,129.16,128.85,128.62,128.19,127.43,127.41,127.10,126.83, 126.66,126.42,125.03,109.19,98.49,86.86,84.75,84.34,83.80,82.08,79.67,75.60,67.20, 59.37,57.51,55.91,52.53,51.26,46.59,44.23,43.83,41.50,40.64,40.20,38.93,38.11,35.77, 35.17,33.79,33.13,32.75,31.95,31.25,27.23,27.08,25.31,21.52,20.67,16.27,16.00,15.85, 13.74,13.21,10.19；
HRMS(ESI)m/z calcd for C75H97FN2NaO17,[M+Na]+1339.6668；Found:1339.6641.
实施例19：称取雷帕霉素(0.05mmol)、靛红3s(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-s1，I-s2，收率85％， dr＝60:40。
产物I-s1结构式为：
I-s1表征为:1H NMR(500MHz,CDCl3)δ7.52(s,2H),7.27–7.21(m,3H),7.18(d,J＝6.9 Hz,1H),7.11(t,J＝7.2Hz,2H),7.00(dd,J＝8.2,2.1Hz,3H),6.46–6.36(m,2H),6.32(dd,J ＝14.8,10.2Hz,1H),6.23(dd,J＝12.7,6.2Hz,1H),6.15(dd,J＝15.1,10.1Hz,1H),5.93(dd, J＝34.5,10.7Hz,1H),5.61–5.47(m,1H),5.42(d,J＝9.9Hz,1H),5.29(d,J＝5.2Hz,1H), 5.16(d,J＝4.3Hz,1H),4.84(s,1H),4.62(d,J＝15.8Hz,1H),4.53(d,J＝15.8Hz,1H),4.23–4.12(m,1H),3.87(s,3H),3.82(dd,J＝10.9,4.5Hz,1H),3.71(d,J＝6.1Hz,1H),3.67(t,J＝ 7.1Hz,1H),3.58(dd,J＝21.3,9.0Hz,1H),3.48(d,J＝12.9Hz,3H),3.44(s,1H),3.40(q,J＝ 4.9Hz,1H),3.34(d,J＝5.4Hz,3H),3.14(d,J＝8.3Hz,3H),2.75(d,J＝6.2Hz,1H),2.72(d, J＝5.9Hz,1H),2.64–2.55(m,1H),2.35(s,1H),2.33(s,1H),2.21(d,J＝11.8Hz,1H),2.04– 1.98(m,1H),1.97(d,J＝4.9Hz,1H),1.88(dd,J＝6.4,3.1Hz,1H),1.86–1.84(m,1H),1.79 (d,J＝6.7Hz,1H),1.76(d,J＝5.2Hz,4H),1.74(s,1H),1.66(s,4H),1.61(dd,J＝6.9,3.7Hz, 3H),1.52(d,J＝5.7Hz,1H),1.50–1.45(m,2H),1.43(d,J＝7.8Hz,1H),1.36–1.31(m,1H), 1.30(dd,J＝7.3,4.2Hz,1H),1.27(s,1H),1.23–1.18(m,1H),1.17(s,1H),1.16(s,1H),1.11 (d,J＝6.7Hz,3H),1.05(dd,J＝16.9,6.7Hz,4H),1.00(d,J＝6.6Hz,3H),0.97(t,J＝6.5Hz, 3H),0.93(d,J＝6.7Hz,3H),0.68(dt,J＝22.1,11.2Hz,1H)；
13C NMR(126MHz,CDCl3)δ215.84,208.20,192.44,175.40,172.32,169.27,166.79,141.52, 140.24,136.09,135.48,134.78,133.67,132.39,130.23,130.17,129.34,128.91,128.64,128.13, 127.80,127.58,127.26,126.88,126.38,109.52,98.48,86.38,84.79,84.40,82.94,81.72,77.79, 75.71,67.17,59.53,56.85,55.88,52.82,51.26,46.57,44.21,43.72,41.41,40.76,40.19,38.83, 38.06,35.66,35.22,33.72,33.08,31.86,31.28,30.36,27.27,27.06,25.29,21.57,20.62,16.27, 16.00,15.95,13.83,13.01,10.30,10.17；
HRMS(ESI)m/z calcd for C75H97ClN2NaO17,[M+Na]+1355.6373；Found:1355.6322.
产物I-s2结构式为：
I-s2表征为:1H NMR(500MHz,CDCl3)δ7.24(dd,J＝4.6,1.9Hz,4H),7.14(dd,J＝18.8, 11.9Hz,4H),7.01(d,J＝2.0Hz,2H),7.00–6.98(m,1H),6.97(s,1H),6.40(dd,J＝14.7,10.6 Hz,1H),6.32(dd,J＝14.8,10.2Hz,1H),6.24(d,J＝8.3Hz,1H),6.20–6.11(m,1H),5.95(dd, J＝33.2,10.6Hz,1H),5.59–5.49(m,1H),5.44(d,J＝9.9Hz,1H),5.35–5.26(m,1H),5.16 (dt,J＝17.5,6.1Hz,1H),4.79(s,1H),4.70–4.54(m,2H),4.27(dd,J＝27.5,5.4Hz,1H),4.20 (d,J＝5.8Hz,1H),3.88(s,3H),3.87(s,1H),3.73(dd,J＝14.6,6.0Hz,1H),3.67(t,J＝7.6Hz, 1H),3.58(d,J＝21.5Hz,3H),3.53(s,1H),3.45(s,1H),3.37(s,1H),3.35–3.32(m,3H), 3.17–3.12(m,3H),2.75(d,J＝5.7Hz,1H),2.72(d,J＝5.7Hz,1H),2.60(dd,J＝16.8,6.4Hz, 1H),2.35(d,J＝14.2Hz,2H),2.19(d,J＝9.4Hz,1H),2.06(d,J＝7.6Hz,1H),2.03–2.00(m, 1H),1.98(d,J＝5.4Hz,1H),1.92–1.85(m,1H),1.79(s,1H),1.77(s,3H),1.75(s,1H),1.69 (s,2H),1.67(s,4H),1.62(dd,J＝10.6,5.0Hz,3H),1.51(d,J＝5.8Hz,1H),1.49(d,J＝5.9Hz, 2H),1.44(d,J＝7.4Hz,1H),1.36–1.33(m,1H),1.33–1.30(m,1H),1.28(s,1H),1.20(d,J＝ 3.2Hz,1H),1.18(s,1H),1.17(d,J＝6.9Hz,1H),1.12(d,J＝6.7Hz,4H),1.08–1.02(m,4H), 1.00(d,J＝6.5Hz,3H),0.97(d,J＝6.6Hz,3H),0.93(d,J＝6.7Hz,3H),0.85(d,J＝6.6Hz, 1H)；
13C NMR(126MHz,CDCl3)δ215.51,208.21,170.59,169.27,166.75,141.62,140.21,136.02, 134.95,133.65,130.17,129.78,129.58,129.17,128.76,128.63,128.23,127.71,127.47,127.11, 126.89,126.68,126.39,109.59,98.50,86.91,84.82,84.36,83.87,81.94,79.60,75.63,67.20, 59.38,57.43,55.89,52.48,51.27,46.58,44.22,43.81,41.46,40.68,40.20,38.92,38.12,35.69, 35.18,33.78,33.14,32.76,31.92,31.26,27.26,27.07,25.30,21.53,20.66,16.26,16.01,15.86, 13.78,13.18,10.33,10.18；
HRMS(ESI)m/z calcd for C75H97ClN2NaO17,[M+Na]+1355.6373；Found:1355.6332.
实施例20：称取雷帕霉素(0.05mmol)、靛红3t(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-t1，I-t2，收率73％， dr＝60:40。
产物I-t1结构式为：
I-t1表征为:1H NMR(400MHz,CDCl3)δ7.52(d,J＝4.6Hz,2H),7.23(d,J＝4.8Hz,3H), 7.19(d,J＝7.0Hz,1H),7.17–7.06(m,3H),7.01(s,2H),6.41(dd,J＝23.1,8.5Hz,2H), 6.35–6.26(m,1H),6.21–6.09(m,2H),5.93(dd,J＝27.6,10.6Hz,1H),5.62–5.46(m,1H), 5.41(d,J＝9.8Hz,1H),5.29(d,J＝4.9Hz,1H),5.16(d,J＝4.4Hz,1H),4.84(s,1H),4.57(dd, J＝32.1,15.8Hz,2H),4.18(d,J＝5.8Hz,1H),3.87(s,3H),3.82–3.77(m,1H),3.72(d,J＝ 5.9Hz,1H),3.67(t,J＝7.5Hz,1H),3.60(d,J＝5.2Hz,1H),3.56(d,J＝5.4Hz,1H),3.49(d,J ＝12.3Hz,3H),3.46(s,1H),3.39(s,1H),3.33(d,J＝6.9Hz,3H),3.14(d,J＝6.3Hz,3H),2.75 (d,J＝5.0Hz,1H),2.71(d,J＝5.1Hz,1H),2.59(dd,J＝16.9,6.2Hz,1H),2.36(s,1H),2.33(s, 1H),2.22(s,1H),2.20(s,1H),2.02(d,J＝5.6Hz,1H),1.98(d,J＝6.1Hz,1H),1.96(s,1H), 1.87(s,1H),1.85(d,J＝4.6Hz,1H),1.81(d,J＝6.3Hz,1H),1.76(s,4H),1.74(s,1H),1.66(s, 4H),1.61(d,J＝9.1Hz,3H),1.52(d,J＝4.1Hz,1H),1.48(d,J＝5.2Hz,2H),1.44(s,1H), 1.34(d,J＝5.4Hz,1H),1.30(d,J＝5.0Hz,1H),1.27(s,1H),1.18(s,1H),1.17(s,1H),1.15(s, 1H),1.10(d,J＝6.6Hz,3H),1.05(dd,J＝12.6,6.7Hz,4H),1.00(d,J＝6.3Hz,3H),0.96(d,J ＝6.6Hz,3H),0.92(d,J＝6.6Hz,3H),0.68(dd,J＝23.9,11.9Hz,1H).
13C NMR(101MHz,CDCl3)δ215.82,208.28,192.48,175.29,172.37,169.28,166.77,142.00, 140.19,136.06,134.71,133.64,132.30,130.24,130.19,129.22,128.66,127.61,127.26,126.91, 126.80,126.41,115.22,110.07,98.46,86.32,84.69,84.38,82.87,81.66,77.79,75.71,67.16, 59.52,57.03,55.92,52.88,51.23,46.59,44.23,43.68,41.46,40.74,40.16,38.83,38.02,35.65, 35.19,33.71,33.05,31.86,31.26,30.34,27.25,27.08,25.30,21.56,20.64,16.30,15.99,15.95, 13.77,13.06,10.19；
HRMS(ESI)m/z calcd for C75H97BrN2NaO17,[M+Na]+1399.5868；Found:1399.5834.
产物I-t2结构式为：
I-t2表征为:1H NMR(400MHz,CDCl3)δ7.54(dd,J＝5.7,3.3Hz,1H),7.27–7.20(m,4H), 7.19–7.10(m,4H),7.01(s,3H),6.40(dd,J＝14.7,10.4Hz,1H),6.36–6.27(m,1H),6.23– 6.17(m,1H),6.15(dd,J＝12.6,7.4Hz,1H),5.95(dd,J＝25.2,10.6Hz,1H),5.55(dd,J＝14.9, 8.8Hz,1H),5.43(d,J＝9.9Hz,1H),5.29(d,J＝4.8Hz,1H),5.22–5.11(m,1H),4.78(s,1H), 4.74–4.50(m,2H),4.31(dd,J＝12.2,5.5Hz,1H),4.23(dd,J＝15.1,5.6Hz,1H),3.87(s,3H), 3.85(s,1H),3.78–3.71(m,1H),3.67(t,J＝7.7Hz,1H),3.57(d,J＝16.6Hz,3H),3.54–3.51 (m,1H),3.51–3.48(m,1H),3.45(d,J＝10.7Hz,1H),3.38(dd,J＝8.4,3.8Hz,1H),3.35(d,J ＝5.1Hz,1H),3.32(d,J＝4.5Hz,3H),3.17–3.11(m,3H),2.79–2.73(m,1H),2.71(d,J＝ 5.4Hz,1H),2.59(dd,J＝16.8,6.4Hz,1H),2.35(d,J＝11.8Hz,2H),2.20(dd,J＝12.5,5.8Hz, 2H),2.07(d,J＝7.4Hz,1H),2.02(dd,J＝12.6,6.8Hz,1H),1.98(d,J＝6.1Hz,1H),1.91– 1.86(m,1H),1.84(d,J＝8.9Hz,1H),1.77(s,3H),1.76(s,1H),1.74(s,1H),1.66(s,4H), 1.65–1.59(m,3H),1.50(d,J＝6.0Hz,1H),1.48(s,2H),1.43(dd,J＝5.6,1.6Hz,1H),1.35– 1.32(m,1H),1.30(d,J＝5.9Hz,1H),1.29(s,1H),1.21–1.19(m,1H),1.17(s,1H),1.15(s, 1H),1.11(d,J＝6.7Hz,3H),1.08–1.02(m,4H),0.99(d,J＝6.5Hz,3H),0.98–0.95(m,3H), 0.93(d,J＝6.8Hz,3H),0.81(d,J＝13.2Hz,1H).
13C NMR(101MHz,CDCl3)δ215.38,208.28,192.74,172.37,170.67,169.30,166.73,142.11, 140.15,135.99,134.92,133.61,132.07,130.48,130.20,130.08,129.52,128.65,128.30,127.48, 127.26,127.14,127.10,126.95,126.59,126.43,114.89,110.13,98.48,86.33,84.73,84.32, 83.92,81.87,79.56,75.63,67.19,59.33,57.43,55.93,52.52,51.25,46.59,44.23,43.78,41.51, 40.65,40.18,38.94,38.06,35.59,35.15,33.80,33.11,32.70,31.93,31.23,27.23,27.10,25.30, 21.52,20.68,16.28,16.16,16.00,15.87,13.69,13.27,10.20；
HRMS(ESI)m/z calcd for C75H97BrN2NaO17,[M+Na]+1399.5868；Found:1399.5857.
实施例21：称取雷帕霉素(0.05mmol)、靛红3u(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-u1，I-u2,收率80％， dr＝71:29。
产物I-u1结构式为：
I-u1表征为:1H NMR(500MHz,CDCl3)δ7.53(s,2H),7.26–7.17(m,5H),7.14(d,J＝6.0 Hz,2H),7.09(d,J＝6.5Hz,2H),6.61–6.50(m,1H),6.39(dd,J＝14.7,10.6Hz,2H),6.30(dd, J＝14.8,10.3Hz,1H),6.24(d,J＝8.2Hz,1H),6.18–6.07(m,1H),5.93(dd,J＝38.8,10.8Hz, 1H),5.57–5.45(m,1H),5.41(d,J＝9.9Hz,1H),5.27(d,J＝5.0Hz,1H),5.15(dd,J＝9.9,5.8 Hz,1H),4.86–4.77(m,1H),4.62(d,J＝14.5Hz,2H),4.23–4.14(m,1H),3.85(dd,J＝8.6, 3.7Hz,1H),3.84–3.80(m,1H),3.77(s,3H),3.74(t,J＝3.8Hz,2H),3.71–3.67(m,1H),3.65 (d,J＝7.7Hz,1H),3.60(s,3H),3.56(s,1H),3.50(s,1H),3.43(d,J＝12.5Hz,1H),3.38(s, 4H),3.34(s,1H),3.33(s,3H),3.13(d,J＝6.4Hz,3H),2.76–2.71(m,1H),2.70(d,J＝5.5Hz, 1H),2.58(dd,J＝16.8,6.3Hz,1H),2.34(s,1H),2.32(s,1H),2.17(s,1H),2.14(s,1H),2.11– 2.05(m,1H),2.02–1.99(m,1H),1.99–1.96(m,1H),1.96–1.90(m,2H),1.86(dd,J＝10.3, 5.7Hz,1H),1.83(d,J＝9.3Hz,1H),1.79(s,1H),1.75(s,4H),1.73(s,1H),1.65(s,4H),1.62– 1.57(m,3H),1.49(d,J＝4.5Hz,1H),1.48(d,J＝8.3Hz,2H),1.44(s,1H),1.35–1.31(m, 1H),1.31–1.28(m,1H),1.27(s,1H),1.18(s,1H),1.16(d,J＝4.4Hz,1H),1.14(s,1H),1.09 (d,J＝6.7Hz,3H),1.05(d,J＝6.6Hz,1H),1.03(d,J＝6.6Hz,3H),0.99(d,J＝6.5Hz,3H), 0.95(d,J＝6.5Hz,3H),0.91(d,J＝6.7Hz,3H),0.68(dt,J＝20.6,10.4Hz,1H).
13C NMR(101MHz,CDCl3)δ215.59,208.24,192.62,175.55,172.00,169.29,166.76,155.58, 140.11,136.64,136.04,135.46,133.59,133.07,130.21,130.14,129.56,128.80,128.55,128.44, 127.41,127.30,126.86,126.76,126.45,113.73,108.81,98.48,85.45,84.73,84.34,82.97,81.75, 77.87,75.71,67.16,59.43,56.77,55.90,55.71,52.62,51.25,46.57,44.21,43.74,41.46,40.74, 40.18,38.88,38.02,35.26,35.18,33.76,33.12,31.83,31.24,30.63,27.23,27.07,25.28,21.54, 20.63,16.27,15.94,13.73,13.10,10.19；
HRMS(ESI)m/z calcd for C76H100N2NaO18,[M+Na]+1351.6868；Found:1351.6844.
产物I-u2结构式为：
I-u2表征为:1H NMR(500MHz,CDCl3)δ7.38–7.30(m,2H),7.21(dd,J＝11.1,6.6Hz,5H), 7.10(dd,J＝20.5,13.3Hz,2H),7.05–6.96(m,2H),6.92(s,1H),6.61–6.53(m,1H),6.51(d, J＝8.5Hz,1H),6.39(dd,J＝14.7,10.7Hz,1H),6.36–6.27(m,1H),6.21(d,J＝8.4Hz,1H), 6.18–6.08(m,1H),5.94(dd,J＝37.9,10.7Hz,1H),5.54(dd,J＝15.1,8.9Hz,1H),5.43(d,J ＝9.8Hz,1H),5.29(d,J＝4.9Hz,1H),5.17(dd,J＝10.2,5.8Hz,1H),4.77(s,1H),4.58(t,J＝ 16.4Hz,2H),4.22(dd,J＝14.5,5.8Hz,1H),3.87(d,J＝7.4Hz,3H),3.78(t,J＝6.8Hz,2H), 3.68(d,J＝7.8Hz,1H),3.65(s,2H),3.63–3.60(m,1H),3.58–3.52(m,3H),3.45(d,J＝4.8 Hz,1H),3.41(dd,J＝10.5,6.4Hz,1H),3.38–3.34(m,1H),3.34–3.30(m,3H),3.17–3.11 (m,3H),2.76–2.71(m,1H),2.70(d,J＝5.6Hz,1H),2.58(dd,J＝16.7,6.6Hz,1H),2.34(d,J ＝11.3Hz,2H),2.15(d,J＝9.4Hz,1H),2.03–1.98(m,1H),1.96(d,J＝11.8Hz,1H),1.92– 1.87(m,1H),1.85(dd,J＝11.2,4.6Hz,1H),1.77(s,4H),1.74(s,1H),1.66(s,4H),1.64–1.58 (m,3H),1.48(m,2H),1.45(s,1H),1.43(d,J＝7.5Hz,1H),1.34(d,J＝5.7Hz,1H),1.30(s, 1H),1.28(s,1H),1.23–1.21(m,1H),1.21–1.17(m,1H),1.16(d,J＝6.8Hz,1H),1.10(d,J＝ 6.8Hz,3H),1.07(d,J＝7.3Hz,1H),1.04(d,J＝6.5Hz,3H),0.99(d,J＝6.5Hz,2H),0.96(d, J＝6.5Hz,3H),0.92(d,J＝6.8Hz,3H),0.81(d,J＝1.0Hz,1H)；
13C NMR(101MHz,CDCl3)δ215.21,208.25,192.78,175.85,170.74,169.29,166.73,140.06, 136.95,136.59,135.96,135.43,134.89,133.57,130.21,129.47,129.04,128.75,128.52,127.42, 127.27,127.14,126.73,126.55,126.47,124.69,109.13,98.49,87.05,84.73,84.29,83.85,82.17, 79.56,75.55,67.19,59.27,57.62,55.91,55.71,52.43,51.26,46.59,44.23,43.77,41.54,40.61, 40.19,38.97,38.15,35.86,35.12,33.82,33.18,32.76,31.82,31.22,27.22,27.07,25.29,21.48, 20.67,16.26,15.98,15.85,13.66,13.29,10.19；
HRMS(ESI)m/z calcd for C76H100N2NaO18,[M+Na]+1351.6868；Found:1351.6840.
实施例22：称取雷帕霉素(0.05mmol)、靛红3v(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-v1，I-v2,收率78％， dr＝70:30。
产物I-v1结构式为：
I-v1表征为:1H NMR(500MHz,CDCl3)δ7.56(d,J＝49.8Hz,2H),7.27(s,1H),7.26–7.21 (m,1H),7.16(dd,J＝14.2,6.8Hz,3H),7.10(d,J＝5.8Hz,2H),6.84(d,J＝7.4Hz,1H),6.59 (d,J＝6.8Hz,1H),6.48(d,J＝11.8Hz,1H),6.44–6.39(m,1H),6.36(d,J＝7.0Hz,1H), 6.35–6.26(m,1H),6.22–6.09(m,1H),6.01–5.88(m,1H),5.54(dt,J＝16.6,10.6Hz,1H), 5.42(d,J＝9.8Hz,1H),5.29(d,J＝5.6Hz,1H),5.23–5.12(m,1H),4.83(d,J＝11.7Hz,1H), 4.68–4.50(m,2H),4.19(dd,J＝15.4,5.3Hz,1H),3.87(d,J＝7.9Hz,1H),3.79(s,3H), 3.77–3.74(m,1H),3.74–3.71(m,1H),3.68(dd,J＝13.4,5.5Hz,1H),3.61(d,J＝7.5Hz, 1H),3.58(s,1H),3.45(d,J＝9.7Hz,1H),3.41(d,J＝7.0Hz,3H),3.37(s,1H),3.35(d,J＝3.8 Hz,3H),3.34–3.30(m,1H),3.14(dd,J＝10.2,4.9Hz,3H),2.75(d,J＝6.0Hz,1H),2.71(d,J ＝5.9Hz,1H),2.64–2.56(m,1H),2.35(s,1H),2.33(s,1H),2.17(d,J＝13.5Hz,1H),2.03– 1.99(m,1H),1.99–1.93(m,1H),1.90–1.85(m,1H),1.84(d,J＝8.9Hz,1H),1.77(s,2H), 1.76(s,3H),1.74(s,1H),1.72–1.69(m,1H),1.67(s,4H),1.62(d,J＝5.5Hz,3H),1.49(d,J＝ 7.2Hz,2H),1.46(s,1H),1.42(dd,J＝12.4,6.4Hz,1H),1.35(dd,J＝10.3,6.5Hz,1H),1.32– 1.30(m,1H),1.29(s,1H),1.19(s,1H),1.17(s,1H),1.14(d,J＝9.2Hz,1H),1.13–1.09(m, 3H),1.09–1.02(m,4H),1.01(dd,J＝6.4,3.9Hz,3H),0.98–0.94(m,3H),0.92(d,J＝6.8Hz, 3H),0.73–0.62(m,1H).
13C NMR(126MHz,CDCl3)δ215.87,208.21,192.62,175.79,172.08,169.28,166.78,140.21, 136.06,135.55,135.21,134.83,133.64,132.69,130.19,130.10,128.71,128.58,127.83,127.65, 127.36,127.02,126.82,126.72,126.41,122.13,109.14,98.48,87.87,84.76,84.38,83.00,81.16, 77.81,75.65,67.18,59.51,56.61,55.88,52.69,51.26,46.56,44.22,43.79,41.44,40.67,40.19, 38.86,38.06,35.23,33.74,33.07,31.76,31.27,30.62,27.26,27.05,25.29,21.56,20.62,16.26, 15.96,15.93,13.81,13.05,10.17；
HRMS(ESI)m/z calcd for C75H97ClN2NaO17,[M+Na]+1355.6373；Found:1355.6328.
产物I-v2结构式为：
I-v2表征为:1H NMR(500MHz,CDCl3)δ7.58–7.44(m,1H),7.40–7.32(m,1H),7.25(t,J ＝8.1Hz,3H),7.14(dd,J＝21.1,7.3Hz,4H),7.02(d,J＝8.3Hz,1H),6.95(s,1H),6.87–6.77 (m,1H),6.40(dd,J＝14.7,10.8Hz,1H),6.34(d,J＝2.3Hz,1H),6.33–6.23(m,1H),6.20– 6.10(m,1H),6.02–5.88(m,1H),5.60–5.48(m,1H),5.42(t,J＝9.5Hz,1H),5.28(t,J＝6.7 Hz,1H),5.18(dd,J＝10.2,6.0Hz,1H),4.80(d,J＝43.4Hz,1H),4.60(dd,J＝37.9,20.9Hz, 2H),4.31(dd,J＝8.6,6.0Hz,1H),4.26–4.16(m,1H),3.86(d,J＝8.0Hz,3H),3.80(s,1H), 3.78–3.74(m,1H),3.74–3.70(m,1H),3.67(t,J＝7.6Hz,1H),3.61(d,J＝9.2Hz,1H), 3.58–3.49(m,3H),3.44(d,J＝12.0Hz,1H),3.42(s,1H),3.35(s,1H),3.34–3.30(m,3H), 3.17–3.12(m,3H),2.78–2.73(m,1H),2.73–2.69(m,1H),2.59(dd,J＝16.8,6.4Hz,1H), 2.35(d,J＝12.1Hz,2H),2.16(d,J＝11.1Hz,1H),2.04(dd,J＝11.3,7.4Hz,1H),2.02–1.99 (m,1H),1.98(s,1H),1.88(dd,J＝13.6,8.7Hz,1H),1.77(s,4H),1.76(s,1H),1.74(s,1H), 1.72(s,2H),1.67(s,4H),1.64–1.59(m,3H),1.48(d,J＝3.2Hz,2H),1.47(s,1H),1.44(d,J＝ 7.6Hz,1H),1.36–1.33(m,1H),1.33–1.29(m,2H),1.28(s,1H),1.23–1.20(m,1H),1.20– 1.17(m,1H),1.17–1.15(m,1H),1.11(d,J＝6.7Hz,3H),1.07(d,J＝6.5Hz,1H),1.05(d,J＝6.5Hz,3H),1.03–0.99(m,3H),0.99–0.95(m,3H),0.92(d,J＝6.7Hz,3H),0.85(d,J＝6.7 Hz,1H).
13C NMR(126MHz,CDCl3)δ215.42,208.15,192.82,170.68,169.28,166.74,144.45,140.14, 136.00,135.15,134.87,133.61,130.19,128.82,128.68,128.45,127.51,127.12,127.06,126.85, 126.64,126.43,122.04,109.16,98.51,87.09,84.81,84.32,83.88,81.48,79.50,75.51,67.21, 59.33,57.43,55.88,52.40,51.29,46.57,44.21,43.84,41.48,40.56,40.21,38.98,38.21,35.84, 35.18,33.81,33.17,32.80,31.79,31.25,27.25,27.05,25.29,21.50,20.65,16.23,15.97,15.85, 13.76,13.20,10.17；
HRMS(ESI)m/z calcd for C75H97ClN2NaO17,[M+Na]+1355.6373；Found:1355.6337.
实施例23：称取雷帕霉素(0.05mmol)、靛红3w(0.10mmol)和辛酸铑(0.0005mmo)，将它们放入反应瓶中，加入2.0mL干燥二氯甲烷，在室温下搅拌5分钟后，称取苯基重氮2a(0.10mmol)溶于干燥二氯甲烷(1.0mL)中，缓慢滴加入反应体系中(约1小时)，继续搅拌半小时，旋蒸去除溶剂，得到粗产品；再通过柱层析(洗脱剂：石油醚：乙酸乙酯＝1：10～1：4)分离出得到雷帕霉素类似物(为一对对映异构体)I-w1，I-w2,收率88％， dr＝63:37。
产物I-w1结构式为：
I-w1表征为:1H NMR(500MHz,CDCl3)δ7.46(s,2H),7.25(dd,J＝9.4,7.1Hz,3H),7.22– 7.16(m,3H),7.08(d,J＝7.2Hz,2H),6.83(dd,J＝9.2,2.9Hz,2H),6.42(s,1H),6.38(dd,J＝ 14.6,3.9Hz,1H),6.31(dd,J＝14.8,10.3Hz,1H),6.15(dd,J＝15.0,10.2Hz,1H),5.93(dd,J ＝35.2,10.7Hz,1H),5.53(dd,J＝15.0,8.8Hz,1H),5.41(d,J＝9.9Hz,1H),5.28(d,J＝5.3 Hz,1H),5.16(dd,J＝10.1,6.0Hz,1H),4.84(t,J＝12.7Hz,2H),4.67(d,J＝15.3Hz,1H), 4.19(dd,J＝16.1,6.2Hz,1H),3.93–3.85(m,1H),3.82–3.75(m,4H),3.72(d,J＝6.1Hz, 1H),3.70–3.64(m,1H),3.58(d,J＝13.1Hz,1H),3.44(t,J＝8.9Hz,2H),3.39(d,J＝3.1Hz, 3H),3.35(d,J＝4.7Hz,4H),3.17–3.11(m,3H),2.74(d,J＝5.7Hz,1H),2.71(d,J＝5.9Hz, 1H),2.59(dd,J＝16.9,6.3Hz,1H),2.34(d,J＝11.8Hz,2H),2.16(d,J＝12.0Hz,1H),2.00 (dd,J＝11.4,5.7Hz,1H),1.95(dd,J＝9.1,6.2Hz,1H),1.90–1.87(m,1H),1.85(dd,J＝6.9, 2.4Hz,1H),1.80(s,1H),1.79(s,1H),1.76(s,3H),1.74(s,1H),1.66(s,4H),1.64–1.58(m, 3H),1.49(d,J＝8.6Hz,2H),1.46(s,1H),1.43(dd,J＝10.0,4.6Hz,1H),1.35(dd,J＝10.6, 6.4Hz,1H),1.30(dd,J＝7.2,4.6Hz,1H),1.27(s,1H),1.18(d,J＝2.6Hz,1H),1.16(s,1H), 1.14(d,J＝6.6Hz,1H),1.10(d,J＝6.7Hz,3H),1.05(dd,J＝16.2,6.6Hz,4H),1.00(dd,J＝ 6.3,3.5Hz,3H),0.96(d,J＝6.6Hz,3H),0.92(d,J＝6.7Hz,3H),0.69(dd,J＝23.8,11.8Hz, 1H).
13C NMR(126MHz,CDCl3)δ215.72,208.22,192.52,175.51,171.95,169.29,166.78,145.81, 140.18,136.43,136.06,135.56,133.63,132.58,130.17,129.97,129.60,128.41,127.71,127.38, 126.80,126.41,122.70,117.57,98.48,86.30,84.75,84.37,83.00,81.47,77.81,75.65,67.18, 59.49,56.62,55.88,52.67,51.26,46.56,45.24,44.21,41.44,40.67,40.18,38.86,38.06,35.21, 33.74,33.08,31.77,31.27,30.55,27.25,27.06,25.28,21.56,20.61,16.26,15.95,13.79,13.05, 10.17；
HRMS(ESI)m/z calcd for C75H97FN2NaO17,[M+Na]+1339.6668；Found:1339.6661.
产物I-w2结构式为：
I-w2表征为:1H NMR(500MHz,CDCl3)δ7.27–7.22(m,3H),7.17(d,J＝7.2Hz,1H),7.15–7.08(m,4H),7.02(t,J＝7.6Hz,2H),6.87–6.79(m,3H),6.40(dd,J＝14.7,10.7Hz,1H),6.32(dd,J＝14.8,10.3Hz,1H),6.20–6.10(m,1H),5.94(dd,J＝40.2,10.8Hz,1H),5.60–5.49(m,1H),5.43(d,J＝10.0Hz,1H),5.29(d,J＝5.1Hz,1H),5.18(dd,J＝10.2,5.5Hz,1H),4.82(dt,J＝26.9,13.4Hz,2H),4.65(d,J＝15.4Hz,1H),4.22(dd,J＝13.2,5.9Hz,1H),3.87(d,J＝7.8Hz,4H),3.81(d,J＝5.8Hz,1H),3.77(d,J＝5.8Hz,1H),3.74–3.70(m,1H),3.67(t,J＝7.6Hz,1H),3.61(d,J＝8.7Hz,1H),3.57–3.51(m,3H),3.47–3.41(m,1H),3.40(d,J＝4.9Hz,1H),3.37(d,J＝4.1Hz,1H),3.36–3.32(m,3H),3.17–3.12(m,3H),2.73(d,J＝5.5Hz,1H),2.70(d,J＝5.5Hz,1H),2.58(dd,J＝16.8,6.6Hz,1H),2.35(d,J＝14.0Hz, 2H),2.14(d,J＝12.9Hz,2H),2.01(s,1H),1.99(d,J＝5.1Hz,1H),1.98(s,1H),1.90–1.87 (m,1H),1.87–1.83(m,1H),1.77(s,4H),1.74(s,1H),1.72(d,J＝4.1Hz,1H),1.67(s,4H), 1.62(dd,J＝12.7,6.2Hz,3H),1.49(d,J＝7.4Hz,2H),1.46(s,1H),1.43(d,J＝3.1Hz,1H), 1.34(d,J＝6.5Hz,1H),1.31–1.29(m,1H),1.28(s,1H),1.21(s,1H),1.19–1.15(m,2H), 1.14–1.09(m,3H),1.08–1.03(m,4H),1.03–0.98(m,3H),0.97(t,J＝5.6Hz,3H),0.92(d,J ＝6.8Hz,4H),0.85(d,J＝6.7Hz,1H).
13C NMR(126MHz,CDCl3)δ215.27,208.21,192.69,175.55,170.37,169.28,166.73,147.72, 145.78,140.09,136.47,135.97,133.58,130.92,130.20,129.48,128.83,128.40,128.36,128.12, 127.71,127.43,127.24,126.60,126.46,123.05,122.71,117.60,117.44,98.49,86.88,84.71, 84.30,83.65,81.89,79.69,75.41,67.20,59.30,57.56,55.90,52.47,51.28,46.60,45.19,44.23, 41.54,40.48,40.20,38.97,38.28,35.14,33.80,33.18,32.77,31.65,31.24,27.25,27.04,25.28, 21.48,20.66,16.25,15.97,15.81,13.72,13.24,10.18；
HRMS(ESI)m/z calcd for C75H97FN2NaO17,[M+Na]+1339.6668；Found:1339.6642.
实施例24：本发明的雷帕霉素类似物对肿瘤细胞株的抑制活性。
MTT法测试化合物抗肿瘤活性：
细胞株名称:A549，Hela,，SKBR3。
实验过程:通过MTT测定评估雷帕霉素及其类似物的细胞毒性。简言之，将三种细胞系以每孔3000至4000个细胞的密度接种在96孔板(Corning，Germany)中。18小时后，用不同浓度的测试化合物处理细胞。进一步温育72小时后，通过加入3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物溶液(5mg/mL，在磷酸盐缓冲盐水中)测定细胞存活率。为了提高测定灵敏度，在甲瓒沉淀溶解于DMSO(生工，中国)后加入25μL Sorensen甘氨酸缓冲液。在570nm处测量吸光度。所有实验一式三份进行。
雷帕霉素及其类似物浓度为5nM时对A549细胞系的细胞毒性，实验结果见图1。
雷帕霉素及其类似物对A549(A)细胞系的IC50测定，实验结果见图2。
雷帕霉素及其类似物对SKBR3细胞系的IC50测定，实验结果见图3。
雷帕霉素及其类似物对Hela细胞系的IC50测定。
以上实验结果表明：与参照化合物雷帕霉素对比，本发明中一些雷帕霉素类似物表现出很好的抗肿瘤活性，可作为有效的抗肿瘤活性化合物应用于医药领域。
Claims (5)
1.一种雷帕霉素类似物，其特征在于，所述雷帕霉素类似物的化学结构如式(I)所示：
其中，R1为为苯基、3-甲氧基苯基、4-氟苯基、3-氟苯基、4-氯苯基；R2为甲氧基；X为氧；R3为氢、不同取代位置的氟、氯、溴、甲氧基、三氟甲基；R4为氢、苄基。
2.如权利要求1所述的雷帕霉素类似物的制备方法，其特征在于，所述方法包括以下步骤：以雷帕霉素、重氮化合物和取代靛红为原料，以金属盐为催化剂，反应得到权利要求1中式(I)的化合物，反应式如下：
所述金属盐为醋酸铑、辛酸铑。
3.如权利要求2所述的方法，其特征在于，溶剂为二氯甲烷、三氯甲烷、四氯甲烷、1,2-二氯乙烷、甲苯、乙酸乙酯中的至少一种；其中，雷帕霉素、重氮化合物、取代靛红、催化剂之间的摩尔比为1.0:(1.0-10.0):(1.0-10.0):(0.001-0.1)。
4.如权利要求3所述的方法，其特征在于，所述雷帕霉素、重氮化合物、取代靛红、催化剂之间的摩尔比为1.0:(2.0-5.0):(2.0-5.0):(0.01-0.1)。
5.如权利要求1所述雷帕霉素类似物在制备抗肿瘤药物中的应用。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009131631A1 (en) * | 2008-04-14 | 2009-10-29 | Poniard Pharmaceuticals, Inc. | Rapamycin analogs as anti-cancer agents |
| EP2298299A2 (en) * | 2000-01-14 | 2011-03-23 | The Trustees Of The University Of Pennsylvania | O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders |
| CN104854112A (zh) * | 2012-11-30 | 2015-08-19 | 杭州归创生物医药有限公司 | 雷帕霉素类似物及其制备方法 |
| CN107735398A (zh) * | 2015-06-23 | 2018-02-23 | 赛比亚斯药业股份公司 | 用于合成雷帕霉素衍生物的方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2009131631A1 (en) * | 2008-04-14 | 2009-10-29 | Poniard Pharmaceuticals, Inc. | Rapamycin analogs as anti-cancer agents |
| CN104854112A (zh) * | 2012-11-30 | 2015-08-19 | 杭州归创生物医药有限公司 | 雷帕霉素类似物及其制备方法 |
| CN107735398A (zh) * | 2015-06-23 | 2018-02-23 | 赛比亚斯药业股份公司 | 用于合成雷帕霉素衍生物的方法 |
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