朱心浩, 张 立, 王 鹏, 李 明
(中国海洋大学海洋药物教育部重点实验室,医药学院,山东 青岛 266003)
薯蓣皂苷元是一种重要的天然甾体皂苷元,主要从薯蓣属植物中分离得到。它是合成甾体激素类药物的重要原料,同时具有抗肿瘤、抗炎、抗氧化等多种显著的药理作用[1]。多个课题组报道,通过对薯蓣皂苷元结构进行改造合成薯蓣皂苷元衍生物,用于进一步研究此类物质的活性[2-5]。2015年本课题组建立了在(PhO)3PAuCl/AgB(C6F5)4催化下,以4,6-O-苄叉甘露糖邻炔基苯甲酸酯为供体,构建β-甘露糖苷键的方法[6]。此外,本课题组以薯蓣皂苷元邻炔基苯甲酸酯作为亲电体和糖醇作为亲核体,发展了金(I)催化合成新型薯蓣皂苷元糖复合物的方法[7]。在此基础上,本文报道金催化的薯蓣皂苷元邻炔基苯甲酸酯与氧、氮、硫和碳亲核体反应,制备薯蓣皂苷元衍生物/异甾体衍生物的方法。
1.2.1 化合物3a和3a′ 称取薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)和2-[2-(2-叠氮乙氧基)乙氧基]乙醇[10](29 mg, 16.7 μmol, 2.0 equiv)加入到含有活化4Å 分子筛的无水三氟甲基苯(2 mL)中,在室温条件下搅拌15 min,然后依次加入AgB(C6F5)4(4.9 mg, 8.4 μmol, 0.1 equiv)和(PhO)3PAuCl (4.7 mg, 8.4 μmol, 0.1 equiv)。 80oC条件下,避光反应5 h后。用三乙胺淬灭反应,反应液用硅藻土助滤,滤液经减压浓缩,硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶6),得到化合物3a(18 mg, 0.031 mmol, 38%)和化合物3a′ (25 mg, 0.044 mmol, 52%)。3a:1H NMR (500 MHz, CDCl3)δ5.38-5.29 (m, 1H), 4.40 (q,J= 6.8 Hz, 1H), 3.75-3.58 (m, 10H), 3.46 (d,J= 9.3 Hz, 1H), 3.38 (d,J= 6.9 Hz, 3H), 3.23-3.12 (m, 1H), 2.37 (d,J= 13.0 Hz, 1H), 2.20 (t,J= 12.3 Hz, 1H), 1.01 (s, 3H), 0.96 (d,J= 6.1 Hz, 3H), 0.78 (s, 6H);13C NMR (126 MHz, CDCl3)δ141.1, 121.4, 109.4, 81.0, 79.6, 71.1, 70.9, 70.8, 70.2, 67.5, 67.0, 62.2, 56.7, 50.8, 50.2, 41.7, 40.4, 39.9, 39.2, 37.4, 37.2, 32.2, 32.0, 31.6, 31.5, 30.4, 28.9, 28.5, 21.0, 19.5, 17.3, 16.4, 14.7.3a′1H NMR (500 MHz, CDCl3)δ4.39 (q,J= 7.4 Hz, 1H), 3.68 (t,J= 4.8 Hz, 5H), 3.65 (d,J= 4.8 Hz, 2H), 3.62 (t,J= 5.0 Hz, 2H), 3.51-3.46 (m, 2H), 3.42-3.33 (m, 3H), 2.88 (s, 1H), 1.01 (s, 3H), 0.96 (d,J= 6.9 Hz, 3H), 0.82 (s, 3H), 0.78 (d,J= 6.2 Hz, 3H), 0.61 (t,J= 4.5 Hz, 1H), 0.39 (dd,J= 8.1, 5.1 Hz, 1H);13C NMR (126 MHz, CDCl3)δ109.3, 81.03, 80.96, 71.2, 70.94, 70.92, 70.2, 68.1, 67.0, 62.4, 56.5, 50.9, 48.2, 43.5, 41.8, 40.9, 40.4, 35.8, 35.6, 33.4, 31.9, 31.6, 30.5, 30.2, 28.9, 25.1, 22.7, 21.7, 17.2, 16.8, 14.7, 13.3。
1.2.2 化合物3b和3b′ 按照合成化合物3a的操作步骤,以薯蓣皂苷元邻炔基苯甲酸酯 (50 mg,83.5 μmol, 1.0 equiv)和N-羟基丁二酰亚胺 (29 mg, 167 μmol, 2.0 equiv)反应后,经硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶10)得到化合物3b(8 mg, 0.016 mmol, 19%)和3b′(17 mg, 0.33 mmol, 40%)。3b:1H NMR (500 MHz, CDCl3)δ5.42-5.32 (m, 1H), 4.40 (q,J= 7.5 Hz, 1H), 4.10-3.97 (m, 1H), 3.54-3.44 (m, 1H), 3.37 (t,J= 11.2 Hz, 1H), 2.72 (s, 4H), 2.49 (t,J= 13.2 Hz, 1H), 2.44-2.33 (m, 1H), 1.04 (s, 3H), 0.97 (d,J= 6.7 Hz, 3H), 0.78 (s, 6H);13C NMR (126 MHz, CDCl3)δ171.8, 139.2, 122.8, 85.9, 80.8, 66.8, 62.1, 56.4, 49.9, 41.6, 39.7, 37.4, 36.7, 32.0, 31.8, 31.4, 30.3, 29.7, 28.8, 27.0, 25.4, 20.9, 17.1, 16.3, 14.5。3b:1H NMR (500 MHz, CDCl3)δ4.40 (q,J= 7.5 Hz, 1H), 3.81 (s, 1H), 3.50-3.43 (m, 1H), 3.37 (t,J= 10.9 Hz, 1H), 2.68-2.60 (m, 4H), 2.46-2.39 (m, 1H), 1.12 (s, 3H), 0.97 (d,J= 7.0 Hz, 3H), 0.90 (s, 3H), 0.79-0.76 (m, 4H), 0.72 (t,J= 4.5 Hz, 1H);13C NMR (126 MHz, CDCl3)δ171.8, 110.2, 109.4, 88.7, 81.1, 67.0, 62.4, 56.2, 47.5, 43.3, 41.8, 40.9, 40.3, 35.5, 33.8, 33.3, 31.64, 31.59, 30.5, 29.5, 29.0, 25.6, 25.2, 24.5, 22.6, 20.0, 17.3, 16.7, 14.7, 12.7。
1.2.3 化合物3c按照合成化合物3a的操作步骤,以薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)和乙酰胺 (8 mg, 100 μmol, 2.0 equiv)反应后,经硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶30)得到化合物3c(19 mg, 0.042 mmol, 49%)。1H NMR (500 MHz, CDCl3)δ4.52 (t,J= 3.0 Hz, 1H), 4.40 (q,J= 7.5 Hz, 1H), 3.51-3.44 (m, 1H), 3.38 (t,J= 10.9 Hz, 1H), 2.05 (s, 3H), 1.02 (s, 3H), 0.97 (d,J= 7.0 Hz, 3H), 0.84 (s, 3H), 0.79 (d,J= 6.3 Hz, 3H)。13C NMR (126 MHz, CDCl3)δ171.0, 109.4, 80.9, 76.1, 67.0, 62.4, 56.3, 47.7, 43.3, 41.8, 40.9, 40.3, 36.5, 35.7, 33.2, 31.9, 31.6, 30.48, 30.47, 24.3, 21.7, 19.6, 17.3, 16.8, 14.7。
1.2.4 化合物3d和3d′ 按照合成化合物3a的操作步骤,薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)与4-甲基苯硫酚 (14 mg, 0.1 mmol, 1.2 equiv)反应,硅胶柱层析 (二氯甲烷∶石油醚 = 1∶2)得到化合物3d(8 mg, 0.015 mmol, 18%)和3d′ (15 mg, 0.029 mmol, 34%)。3d:1H NMR (500 MHz, CDCl3)δ7.30 (d,J=7.9 Hz, 2H), 7.10 (d,J= 7.8 Hz, 2H), 5.32-5.24 (m, 1H), 4.46-4.35 (m, 1H), 3.55-3.43 (m, 1H), 3.37 (t,J= 10.9 Hz, 1H), 3.00-2.85 (m, 1H), 2.33 (s, 3H), 2.31-2.26 (m, 2H), 0.99 (s, 3H), 0.97 (d,J= 6.9 Hz, 3H), 0.82-0.74 (m, 6H);13C NMR (126 MHz, CDCl3)δ142.0, 137.0, 132.8, 131.0, 129.7, 120.9, 109.4, 80.9, 67.0, 62.2, 56.7, 50.4, 47.9, 41.7, 40.4, 39.9, 39.8, 39.7, 37.1, 32.1, 32.0, 31.53, 31.50, 30.5, 29.6, 29.0, 21.2, 20.8, 19.5, 17.3, 16.4, 14.7. 3d′:1H NMR (500 MHz, CDCl3)δ7.64 (d,J= 7.9 Hz, 1H), 7.28 (d,J= 8.2 Hz, 1H), 7.21 (t,J= 7.5 Hz, 1H), 7.08 (t,J= 7.4 Hz, 1H), 6.84 (s, 1H), 5.39-5.38 (m, 1H), 4.44 (q,J= 7.5 Hz, 1H), 3.75 (s, 3H), 3.48 (dd,J= 10.1, 2.7 Hz, 1H), 3.39 (t,J= 10.9 Hz, 1H), 2.83 (t,J= 12.3 Hz, 1H), 2.56-2.43 (m, 1H), 2.43-2.37 (m, 1H), 1.11 (s, 3H), 0.99 (d,J= 6.9 Hz, 3H), 0.82 (s, 3H), 0.80 (d,J= 6.3 Hz, 3H);13C NMR (126 MHz, CDCl3)δ159.1, 144.6, 118.6, 115.4, 109.4, 91.4, 81.1, 67.0, 62.3, 56.8, 55.9, 55.4, 50.5, 41.8, 40.4, 40.2, 40.1, 37.5, 36.1, 35.5, 32.3, 32.0, 31.7, 31.6, 30.5, 29.0, 25.9, 20.9, 19.6, 17.3, 16.5, 14.7。
1.2.5 化合物3e和3e′ 按照合成化合物3a的操作步骤,以薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)和N-甲基吲哚 (14 μL, 0.1 mmol, 1.2 equiv)反应后,经硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶40)得到化合物3e(13 mg, 0.025 mmol, 30%)和3e′(7 mg, 0.013 mmol, 16%)。3e:1H NMR (500 MHz, CDCl3)δ7.64 (d,J= 7.9 Hz, 1H), 7.28 (d,J= 8.2 Hz, 1H), 7.21 (t,J= 7.5 Hz, 1H), 7.08 (t,J= 7.4 Hz, 1H), 6..84 (s, 1H), 5.39 (d,J= 4.5 Hz, 1H), 4.44 (q,J= 7.5 Hz, 1H), 3.75 (s, 3H), 3.48 (dd,J= 10.1, 2.7 Hz, 1H), 3.39 (t,J= 10.9 Hz, 1H), 2.83 (t,J= 12.3 Hz, 1H), 2.56-2.43 (m, 1H), 2.43-2.37 (m, 1H), 1.11 (s, 3H), 0.99 (d,J= 6.9 Hz, 3H), 0.82 (s, 3H), 0.80 (d,J= 6.3 Hz, 3H);13C NMR (126 MHz, CDCl3)δ143.5, 127.2, 124.4, 121.6, 119.7, 119.5, 118.6, 109.4, 109.3, 81.0, 67.0, 62.3, 56.7, 50.6, 41.8, 40.5, 40.1, 40.0, 37.5, 37.1, 32.7, 32.3, 32.0, 31.7, 31.59, 31.57, 30.5, 30.4, 30.0, 29.9, 29.0, 20.9, 19.9, 17.3, 16.5, 14.7.3e:1H NMR (500 MHz, CDCl3)δ7.59 (d,J= 8.0 Hz, 1H), 7.26 (d,J= 3.2 Hz, 2H), 7.17 (t,J= 7.6 Hz, 1H), 7.09 (s, 1H), 7.01 (t,J= 7.5 Hz, 1H), 4.42 (dd,J= 8.4, 5.9 Hz, 1H), 3.76 (s, 3H), 3.46 (dd,J= 7.1, 4.7 Hz, 1H), 3.37 (t,J= 11.1 Hz, 1H)2.75 (d,J= 5.4 Hz, 1H), 2.50-2.47 (m, 1H), 2.08 (t,J= 7.2 Hz, 1H), 1.05 (s, 3H), 0.96 (d,J= 6.8 Hz, 3H), 0.77 (d,J= 6.4 Hz, 3H), 0.68-0.66 (m, 4H), 0.44-0.41 (m, 1H);13C NMR (126 MHz, CDCl3)δ137.1, 128.1, 121.1, 120.2, 118.4, 110.2, 109.3, 109.1, 81.0, 67.0, 62.5, 56.6, 48.5, 43.6, 41.8, 40.7, 40.3, 38.7, 36.5, 35.6, 32.8, 32.0, 31.5, 30.4, 29.9, 28.9, 27.6, 25.1, 22.6, 22.2, 17.3, 16.8, 14.7, 13.5。
图 1 薯蓣皂苷元衍生物的合成Fig. 1 Synthesis of diosgenin derivatives
1.2.6 化合物3f按照合成化合物3a的操作步骤,以薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)和1,3-二甲氧基苯2f[11](13 mg, 0.1 mmol, 1.2 equiv)反应后,经硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶60)得到化合物3f(22 mg, 0.041 mmol, 49%)。1H NMR (500 MHz, CDCl3)δ7.10 (t,J= 8.3 Hz, 1H), 6.54 (d,J= 8.3 Hz, 2H), 5.30 (s, 1H), 4.42 (q,J= 7.4 Hz, 1H), 3.79 (s, 6H), 3.53-3.44 (m, 1H), 3.39 (t,J= 10.9 Hz, 1H), 3.30-3.23 (m, 1H), 3.11 (t,J= 13.2 Hz, 1H), 2.44-2.35 (m, 1H), 1.12 (s, 3H), 0.98 (d,J= 6.9 Hz, 3H), 0.81 (s, 3H), 0.80 (d,J= 6.4 Hz, 3H);13C NMR (126 MHz, CDCl3)δ144.5, 126.9, 122.8, 118.8, 109.4, 104.76, 104.75, 81.1, 67.0, 62.3, 56.9, 55.9, 50.5, 41.8, 40.5, 40.2, 40.1, 37.5, 35.9, 35.7, 32.3, 32.1, 31.8, 31.6, 30.5, 29.9, 29.0, 25.5, 20.9, 19.7, 17.3, 16.5, 14.7。
1.2.7 化合物3g按照合成化合物3a的操作步骤,以薯蓣皂苷元邻炔基苯甲酸酯 (50 mg, 83.5 μmol, 1.0 equiv)和丙二腈2g(56 mg, 0.835 mmol, 10 equiv)反应后,经硅胶柱层析 (乙酸乙酯∶石油醚 = 1∶15)得到化合物3g(32 mg, 0.039 mmol, 94%)。1H NMR (500 MHz, CDCl3)δ5.39-5.28 (m, 1H), 4.44-4.36 (m, 1H), 3.50-3.43 (m, 1H), 3.37 (t,J= 10.9 Hz, 1H), 3.31-3.21 (m, 1H), 1.01(s, 3H), 0.97 (d,J= 6.9 Hz, 3H), 0.79 (d,J= 5.4 Hz, 3H), 0.78 (s, 3H);13C NMR (126 MHz, CDCl3)δ141.3, 121.0, 109.3, 80.8, 76.3, 66.8, 62.1, 56.5, 50.2, 41.6, 40.3, 40..0, 39.8, 37.4, 37.0, 32.1, 31.8, 31.44, 31.37, 30.3, 29.4, 28.8, 20.8, 19.4, 17.1, 16.3, 14.5。
如图1所示,以三氟甲基苯作为溶剂,(PhO)3PAuCl/AgB(C6F5)4作为催化剂,薯蓣皂苷元邻炔基苯甲酸酯1与氧亲核试剂2-[2-(2-叠氮乙氧基)乙氧基]乙醇2a进行反应,分别以38%的收率得到了3位连接的薯蓣皂苷元衍生物3a和52%的收率得到了6位连接的异甾体产物3a′,这是由于亲核试剂分别进攻高烯丙基碳正离子3位和6位造成的。以N-羟基丁二酰亚胺2b为氧亲核试剂时,以19%的收率得到了3位连接的薯蓣皂苷元衍生物3b和40%的收率得到了6位连接的异甾体产物3b′。为了进一步研究此反应的适用性,本文以乙酰胺2c作为氮亲核试剂与化合物1反应,以49%的收率得到单一产物异甾体衍生物3c′;当以对甲基苯硫酚2d作为硫亲核试剂与化合物1进行反应时,以18%的收率得到薯蓣皂苷元衍生物3d和34%的收率得到异甾体产物3d′。碳亲核试剂也被用于薯蓣皂苷元的官能团化研究。当N-甲基吲哚2e为碳亲核试剂时,以30%的收率得到薯蓣皂苷元衍生物3e和16%的收率得到异甾体产物3e′;而当1,3-二甲氧基苯2f为碳亲核试剂时,以49%的产率生成薯蓣皂苷元衍生物3f;当以丙二腈2g为碳亲核试剂时,没有得到期望的薯蓣皂苷元衍生物3g, 而以94%的收率得到薯蓣皂苷元的二聚体化合物3h。
本文以薯蓣皂苷元邻炔基苯甲酸酯为原料,在(PhO)3PAuCl和AgB(C6F5)4的催化下,通过在3/6位形成碳氧键,碳氮键,碳硫键和碳碳键,合成了新型的薯蓣皂苷元衍生物;为薯蓣皂苷元的结构修饰提供了一条新的途径。
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