CN108997448B - 一种吡喃糖环吡咯螺缩酮生物碱的全合成方法及应用 - Google Patents
一种吡喃糖环吡咯螺缩酮生物碱的全合成方法及应用 Download PDFInfo
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- CN108997448B CN108997448B CN201810783547.1A CN201810783547A CN108997448B CN 108997448 B CN108997448 B CN 108997448B CN 201810783547 A CN201810783547 A CN 201810783547A CN 108997448 B CN108997448 B CN 108997448B
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Abstract
本发明属于化学合成技术领域，提供了一种吡喃糖环吡咯螺缩酮生物碱的全合成方法及应用。以D‑葡萄糖为原料，与二苄胺反应生成果糖二苄胺，经异丙叉保护，Pd/C脱氢还原得到氨基果糖。二氢吡喃酮与氨基果糖进行Maillard缩合反应，随后在酸性条件完成螺环化反应，得到互为非对映异构体的一对环合产物，直接于酸性条件下脱除异丙叉基保护基，得到吡喃糖环吡咯螺缩酮生物碱的3‑羟基类似物。将环合产物分别经Barton‑McCombie反应脱除3‑羟基，再于酸性条件下脱除异丙叉基保护基，得到吡喃糖环吡咯螺缩酮生物碱。本发明的吡喃糖环吡咯螺缩酮生物碱用于抗衰老抗氧化相关药物及化妆品中。
Description
技术领域
本发明属于化学合成技术领域，具体为一种吡喃糖环吡咯螺缩酮生物碱的全合成方法及应用。
技术背景
吡咯螺缩酮类生物碱从其最初于蒙古黄芪中提取发现已有15年的历史，这期间人们陆续在油菜花粉、石菖蒲、刺山柑等传统中草药以及全麦面包、黑柄炭角菌、中成药参松养心胶囊中提取发现此类生物碱。这类生物碱所来源的中草药或药用真菌都有着明显的抗氧化、抗病毒、降血脂、抗高血糖等作用，且在有限的活性研究中也发现吡咯螺缩酮生物碱有着普遍且明显的抗氧化活性。这类生物碱在植物体内含量稀少，提取困难，活性明显，同时其特殊的吗啉环结构也是多种酶抑制剂的主要药效团。自2011年Sudhakar等人首次合成Acortatarin A和B以来，至今已有10余篇文献采用不同的路线对吡咯螺缩酮生物碱进行了全合成。寻找一种环境友好、步骤简便、方便廉价的合成路线是近些年来很多药物化学工作者一直在探索的课题。然而，现有的合成路线大多繁杂，无法简便廉价的得到天然生物碱，同时Maillard反应作为构建吡咯螺缩酮生物碱关键中间体N-取代5-羟甲基-吡咯-2-甲醛结构的手段，具有显著的方便有效的优点，这很有可能成为打开吡咯螺缩酮生物碱生物合成途径的钥匙，却并未引起大家足够的重视。
发明内容
本发明的目的在于提供Pollenopyrroside A和Shensongine A及类似物的一种合成方法，以D-葡萄糖为原料，与二苄胺反应生成果糖二苄胺，经异丙叉保护，Pd/C脱氢还原得到氨基果糖。二氢吡喃酮与氨基果糖进行Maillard缩合反应，随后在酸性条件完成螺环化反应，得到互为非对映异构体的一对环合产物，直接于酸性条件下脱除异丙叉基保护基，得到Pollenopyrroside A和Shensongine A的3-羟基类似物。将环合产物分别经Barton-McCombie反应脱除3-羟基，再于酸性条件下脱除异丙叉基保护基，得到PollenopyrrosideA和Shensongine A。
本发明的技术方案如下：
一种吡喃糖环吡咯螺缩酮生物碱的全合成方法，步骤如下：
以D-葡糖为原料，乙酸等有机酸提供酸性条件，反应温度为50～80℃，反应时间2～5h，与二苄胺进行Amadori重排反应，得到化合物I；
由盐酸、硫酸等无机酸或H型阳离子交换树脂提供酸性条件，丙酮作为溶剂，反应温度为-10～25℃，反应时间为2～5h，化合物I的羟基用异丙叉基保护，得到化合物II；
以钯碳为催化剂，溶剂选择甲醇、乙醇等，反应温度为10～35℃，反应时间为6～24h，化合物II的苄基进行加氢还原，得到化合物III；
在酸性条件下，化合物III与二氢吡喃酮进行Maillard缩合反应，得到化合物IV：酸性条件可由乙酸等质子酸或氯化锌等路易斯酸提供，溶剂可选择二氧六环、二甲基亚砜、乙醇等，反应温度为15℃～100℃，反应时间为8～24h。
化合物IV在酸性条件下螺环化得到化合物V和化合物VI：酸性试剂可选择对甲苯磺酸、氨基磺酸、樟脑磺酸等，溶剂为二氯甲烷，反应温度为-10～10℃，反应时间为2～5h。
化合物V或化合物VI脱除异丙叉基保护，得到Pollenopyrroside A或ShensongineA的类似物化合物VII和化合物VIII，采用下述一种方法：
A.溶剂及催化剂为30％～80％乙酸，反应温度为10～30℃，反应时间为2～6h；
B.催化剂为盐酸，溶剂为甲醇或乙醇，反应温度为-10～10℃，反应时间为2～6h；
化合物V或化合物VI裸露的羟基通过Barton-McCombie反应脱除，得到化合物IX或化合物XI：该反应的催化剂为咪唑，溶剂为四氢呋喃，化合物V或化合物VI与氢化钠，二硫化碳和碘甲烷反应成黄原酸酯，反应温度为10～35℃，反应时间为0.5～6h，分离纯化得化合物IX或化合物XI，在二氧六环为溶剂，过氧化苯甲酰为自由基引发剂，三乙基硅烷作用下脱除黄原酸酯，得到化合物X或化合物XII，反应温度为80～101℃，反应时间为0.5～6h。
化合物X或化合物XII在酸性条件下脱除异丙叉基保护基，得到最终产物Pollenopyrroside A或Shensongine A：采用下述一种方法：
A.溶剂及催化剂为30％～80％乙酸，反应温度为10～30℃，反应时间为2～6h；
B.催化剂为盐酸，溶剂为甲醇或乙醇，反应温度为-10～10℃，反应时间为2～6h；
本发明的全合成方法使用Maillard反应作为构建关键中间体，步骤大大简便，原料方便廉价，环境友好，可用于抗衰老抗氧化相关药物及化妆品的开发与研究。
本发明采用人宫颈癌HeLa细胞中缺氧诱导的HIF-1抑制活性的评价方法。该方法将共转染有以慢病毒颗粒为载体的HRE-Luc和CMV-Luc报告基因的Hela细胞复苏后培养于DMEM培养基中，种于96孔板，利用酶标仪先后检测各孔的HRE-Luc和CMV-Luc值。本发明通过该评价方法表明Pollenopyrroside A(IC50≥30μM)和化合物VII(10μM≤IC50≤30μM)均具有较强的HIF-1抑制活性，且化合物VII的抑制效果更强。
本发明采用单线态氧清除活性实验。单线态氧1O2是一种重要的活性氧(Reactiveoxygen species，ROS)，可以造成机体的损伤，引发衰老及相关疾病。适量清除体内单线态氧可以达到预防或治疗的作用。化合物的抗衰老活性与其抗氧化活性息息相关，而抗氧化活性包括了清除单线态氧，清除氧自由基等作用。本发明引用本课题组曹志博士的实验方法采用新型铕配合物单线态氧荧光探针ATTA-Eu3+(4′-(9-蒽基)-2,2′:6′,2″-联三吡啶-6,6″-二甲胺四乙酸-Eu3+)检测单线态氧。该探针几乎不发荧光，与单线态氧特异性反应生成内氧化物后，其荧光量子产率增加17倍，变为强荧光性物质。用时间分辨荧光测定仪测定其荧光强度的改变。本发明通过该实验表明Pollenopyrroside A和化合物VII均具有一定程度的清除单线态氧能力，有着显著的抗氧化抗衰老活性。
附图说明
图1是新型铕配合物单线态氧荧光探针检测超声辐照下单线态氧含量。
图2是Pollenopyrroside A和化合物VII对单线态氧的清除率。
具体实施方式
下面结合实施例对本发明做进一步详细的描述，但本发明的实施方式不限于此。
化合物I的制备：称量10.0g D-葡萄糖加入500mL三口烧瓶中，依次加入120mL无水乙醇，搅拌均匀，之后称取二苄胺(11.0g,55.56mmol,1equiv)，加入反应瓶中，加入3mL冰乙酸，加热至80℃，回流搅拌，反应3h，待其冷却至室温后，过滤，乙醇多次洗涤滤渣，得白色针状固体16.9g，收率86％。1H NMR(400MHz,DMSO)δ7.30(dt,J＝23.2,7.2Hz,10H,Ph-H),5.25(s,1H,13-OH),4.43(d,J＝4.7Hz,1H,-OH),4.38(d,J＝2.7Hz,1H,-OH),4.15(t,J＝6.5Hz,1H,-OH),3.81(d,J＝12.0Hz,1H,H-3),3.74(d,J＝13.8Hz,2H,H-13),3.63(d,J＝13.8Hz,2H,H-15),3.63(1H,H-4),3.58(d,J＝2.3Hz,2H,H-2),3.43(d,J＝12Hz,1H,H-5),2.68(q,J＝13.3Hz,2H,H-11).
化合物II的制备：在500mL的三口瓶中加入化合物I(10.8g,30mmol)，加入300mL丙酮，氮气置换三次，恒压滴液漏斗缓慢滴加2.5mL浓盐酸，约10min滴完，溶液逐渐变澄清，室温反应2.5h，TCL(二氯甲烷：甲醇＝20：1)检测，原料消失，25％-28％氨水中和反应液中的酸，至pH为中性时为止，过滤，旋转蒸发除去丙酮溶剂，3x100mL二氯甲烷萃取，2x50mL饱和食盐水洗涤，干燥有机相，浓缩有机相后硅胶柱层析，洗脱剂为二氯甲烷：甲醇＝50：1，得到无色油状物，隔膜泵抽走残留溶剂，冷藏干燥，得无色固体粉末10.3g，收率86％。1H NMR(400MHz,DMSO)δ7.37–7.21(m,10H,Ph-H),5.54(d,J＝1.1Hz,1H,-OH),4.78(d,J＝6.6Hz,1H,-OH),4.13(dd,J＝5.7,2.3Hz,1H,H-3),4.03–3.93(m,2H,H-2),3.75(d,J＝14Hz,2H,H-11),3.75(1H,H-4),3.60(d,J＝14Hz,2H,H-9),3.45(t,J＝7.3Hz,1H,H-5),2.69(s,2H,H-7),1.38(s,3H,H-18),1.26(s,3H,H-19).
化合物III的制备：称取化合物II(10.4g,26.07mmol)，加入500mL的圆底烧瓶中，加入170mL乙醇溶解，N2置换保护三次，加入10％Pd/C 1.6g，H2置换保护三次，常温反应12小时后，TLC(氯仿：甲醇：水＝12:6:1)原料点消失，硅藻土助滤，过滤除Pd/C，蒸除乙醇溶剂，300mL二氯甲烷：正己烷＝1：1溶解(每1.2g产物需60mL溶剂)，重结晶得到白色固体5.2g，收率93％。1H NMR(400MHz,DMSO)δ4.14(dd,J＝5.6,2.6Hz,1H,H-3),3.97(m,2H,H-2),3.74(d,J＝13.2Hz,1H,H-4),3.37(d,J＝7.7Hz,1H,H-5),2.61(s,2H,H-7),1.39(s,1H,H-14),1.25(s,3H,H-15).
化合物IV的制备：称取化合物III(1.2g,5.83mmol，1.2equiv)，用150mL1，4-二氧六环超声震荡溶解，称取二氢吡喃酮(0.7g,4.86mmol，1equiv)，溶于50mL 1，4-二氧六环溶剂中，将以上溶液混合，置于500mL圆底烧瓶中，加入20mL冰乙酸，氮气置换三次，室温搅拌反应，约12小时后，TLC检测(氯仿：甲醇：水＝10：3：1)原料消失，停止反应，旋转蒸发除去二氧六环溶剂，硅胶柱层析(二氯甲烷：甲醇＝50：1)，得到0.9g无色油状物，收率53％。1H NMR(400MHz,CDCl3)δ9.35(s,1H,H-20),7.03(d,J＝4.1Hz,1H,H-17),6.37(d,J＝4.1Hz,1H,H-18),4.68(s,2H,H-22),4.64(d,J＝15.2Hz,1H,H-14),4.53(d,J＝15.2Hz,1H,H-14),4.23–4.12(m,3H,H-2,H-3),3.95(d,J＝13.1Hz,1H,H-4),3.64(d,J＝4.6Hz,1H,H-5),1.49(s,3H,H-10),1.36(s,3H,H-11).13C NMR(100MHz,CDCl3)δ181.13(s),145.85(s),133.07(s),127.51(s),112.19(s),109.32(s),96.34(s),73.06(s),72.60(s),59.81(s),56.00(s),53.46(s),51.05(s),27.91(s),26.07(s).
化合物V和化合物VI的制备：称取化合物IV(160mg,0.5mmol)溶于40mL二氯甲烷中，冰浴下搅拌20min后加入20mg对甲苯磺酸，冰浴下反应1.5h，TLC检测(氯仿：甲醇：水＝10：3：1)反应完成，原料消失，加入20mL饱和NaHCO3溶液中和至中性，3x30mL二氯甲烷萃取，干燥有机相，旋转蒸发除去二氯甲烷溶剂，硅胶柱层析，洗脱剂为石油醚：乙酸乙酯＝3：1，分别得到68mg、37mg的白色固体化合物V和化合物VI，收率分别为54％和25％。化合物V:1HNMR(400MHz,CDCl3)δ9.47(s,1H,H-15),6.95(d,J＝4.1Hz,1H,H-13),6.03(d,J＝4.1Hz,1H,H-12),5.01(d,J＝15.4Hz,1H,H-11a),4.92(d,J＝15.4Hz,1H,H-11b),4.69(d,J＝14.5Hz,1H,H-3),4.45(dd,J＝13.1,6.0Hz,2H,H-8a,8b),4.26(t,J＝7.0Hz,1H,H-4),4.02(d,J＝7.3Hz,1H,H-5),3.90(ddd,J＝17.9,12.2,5.6Hz,2H,H-2a,2b),1.56(s,3H,H-21),1.41(s,3H,H-22).13C NMR(100MHz,CDCl3)δ178.88(s),134.77(s),131.24(s),124.42(s),110.45(s),104.86(s),96.38(s),76.08(s),73.20(s),71.02(s),61.56(s),58.46(s),46.46(s),27.71(s),25.52(s).化合物VI:1H NMR(400MHz,CDCl3)δ9.48(s,1H,H-16),6.94(d,J＝4.1Hz,1H,H-13),6.04(d,J＝4.1Hz,1H,H-12),4.95(d,J＝15.2Hz,1H,H-11a),4.87(d,J＝15.2Hz,1H,H-11b),4.60(s,2H,H-8a,8b),4.31(m,2H,H-2a,2b),4.10(d,J＝13.3Hz,1H,H-5),3.98(dd,J＝13.3,1.7Hz,1H,H-4),3.77–3.73(m,1H,H-3),1.59(s,3H,H-21),1.41(s,3H,H-22).13C NMR(100MHz,CDCl3)δ178.89(s),133.49(s),131.45(s),124.02(s),109.70(s),104.94(s),95.75(s),76.27(s),73.22(s),71.88(s),60.45(s),58.06(s),48.85(s),28.05(s),26.11(s).
化合物VII和化合物VIII制备：称取化合物V(62mg,0.2mmol)溶于30mL80％乙酸中，置于100ml茄形瓶中，30℃搅拌反应3.5h，TCL(甲醇：乙酸乙酯＝5：
1)检测原料消失，停止反应，加入甲苯旋转蒸发带出乙酸，残余物硅胶柱层析，二氯甲烷：甲醇＝10：1洗脱，得白色固体43mg，收率80％。1H NMR(400MHz,DMSO)δ9.41(s,1H,H-15),7.02(d,J＝4.1Hz,1H,H-13),6.06(d,J＝4.1Hz,1H,H-12),5.56(d,J＝5.7Hz,1H,-OH),4.86(d,J＝16.0Hz,1H,H-11a),4.68(d,J＝16.0Hz,1H,H-11b),4.62(d,J＝6.4Hz,1H,H-3),4.49(dd,J＝9.9,4.5Hz,2H,H-8a,8b),3.98(d,J＝14.6Hz,1H,-OH),3.85-3.77(m,1H,H-4),3.70(ddd,J＝9.5,7.0,3.9Hz,2H,H-2a,2b),3.63(t,J＝10.3Hz,1H,H-5),3.36(dd,J＝10.6,4.7Hz,1H,-OH).化合物VIII的制备合成步骤参照化合物VII的合成方法，收率87％。
1H NMR(400MHz,DMSO)δ9.44(s,1H,H-15),7.03(d,J＝4.0Hz,1H,H-13),6.08(d,J＝4.0Hz,1H,H-12),5.16(d,J＝7.0Hz,1H,-OH),4.90(d,J＝15.8Hz,1H,H-11a),4.74(d,J＝5.8Hz,1H,-OH),4.67(m,2H,H-11b,H-3),4.37(d,J＝14.0Hz,1H,H-8a),4.24(d,J＝14.0Hz,1H,H-8b),3.75(m,1H,H-4),3.70(ddd,J＝9.4,5.9,3.4Hz,1H,H-3),3.64(d,J＝12.1Hz,1H,-OH),3.59–3.50(m,2H,H-2a,2b).
化合物IX或化合物XI的制备：称取化合物VII(37.3mg,0.12mmol)及1mg咪唑，加入50mL三口瓶中，通入氮气，再加20mL无水四氢呋喃，冰水浴下搅拌20分钟，反应液呈淡黄色。称取60％氢化钠(10mg,0.24mmol，2equiv)，分批加入，反应液产生大量气泡并变灰色，全部加完后继续搅拌40min。撤下冰水浴，称取CS2(22μL,0.36mmol，3equiv)，缓慢滴加，保持反应温度在35℃以内，此时，反应液瞬间变黄色，滴加完毕后继续搅拌60min。再加入碘甲烷(15μL,0.24mmol，2equiv)，搅拌30min。TLC(石油醚：乙酸乙酯＝2：1)检测至反应终点。滴加1mL冰醋酸去除过量的氢化钠。旋干反应液，得到黄色半固体状态物质，用50mL乙醚溶解，用饱和NaCO3水溶液洗涤(50mL×2次)，有机层用无水硫酸钠干燥，过滤，蒸干得浅黄色糖浆状物质。粗产物硅胶柱层析，石油醚：乙酸乙酯＝6:1洗脱，得白色固体粉末44.3mg，收率92％。1HNMR(400MHz,CDCl3)δ9.46(s,1H,H-15),6.92(d,J＝4.1Hz,1H,H-13),6.21(d,J＝4.4Hz,1H,H-5),6.01(d,J＝4.1Hz,1H,H-12),4.99–4.86(m,2H,H-11a,11b),4.76(d,J＝14.3Hz,1H,H-3),4.40(m,2H,H-8a,8b),4.14(d,J＝14.3Hz,1H,H-4),3.89(qd,J＝12.1,6.4Hz,2H,H-2a,2b),2.63(s,3H,H-26),1.56(s,3H,H-21),1.37(s,3H,H-22).13C NMR(100MHz,CDCl3)δ215.37(s),178.84(s),134.05(s),131.24(s),124.10(s),110.63(s),104.88(s),95.06(s),78.27(s),73.29(s),69.69(s),61.02(s),58.30(s),47.99(s),27.57(s),25.84(s),19.62(s).HRMS(ESI)calcd for C17H21NO6S2[M+H]+400.0888,found 400.0844.化合物XI的制备合成步骤参照化合物IX的合成方法，收率95％。1H NMR(400MHz,CDCl3)δ9.46(s,1H,H-15),6.90(d,J＝4.1Hz,1H,H-13),6.16(d,J＝7.8Hz,1H,H-5),6.02(d,J＝4.1Hz,1H,H-12),4.95(d,J＝15.3Hz,1H,H-11a),4.84(d,J＝15.3Hz,1H,H-11b),4.65(d,J＝14.4Hz,1H,H-3),4.55(dd,J＝7.6,5.6Hz,1H,H-8a),4.35(dd,J＝5.3,2.4Hz,1H,H-8b),4.17(d,J＝14.1Hz,2H,H-2a,2b),4.00(dd,J＝13.5,2.7Hz,1H,H-4),2.59(s,3H,H-26),1.60(s,3H,H-20),1.38(s,3H,H-21).13C NMR(100MHz,CDCl3)δ216.59(s),178.69(s),133.09(s),131.50(s),123.60(s),110.14(s),104.95(s),95.79(s),79.54(s),73.78(d,J＝25.5Hz),60.41(s),58.37(s),48.39(s),27.62(s),26.37(s),21.07(s),19.57(s),14.21(s).HRMS(ESI)calcd for C17H21NO6S2[M+H]+400.0885,found 400.0844.
化合物X或化合物XII的制备：称取化合物IX(100mg,0.25mmol)，加入干燥的50mL三口瓶中，加入15mL二氧六环，氮气置换三次，搅拌均匀，再加入三乙基硅烷(148μL,1.25mmol，5equiv)，称取过氧化苯甲酰(45mg,0.25mmol，1equiv)，用5mL二氧六环溶解，置于恒压滴液漏斗中，加热至回流，20min后，缓慢滴加BPO的二氧六环溶液，约10min加完。滴加完成后，反应液呈浅黄色，继续回流60min，TLC(石油醚：乙酸乙酯＝3：1)检测至反应终点。反应结束后冷却至室温，缓慢滴加氢氧化钠溶液调节pH至弱碱性，反应液呈亮黄色。用氯仿15mL×3次萃取，有机层显浅黄色，有机层用水反洗25mL×3次，之后用无水硫酸钠干燥，过滤，蒸干，得淡黄色黏性液体。粗产物硅胶柱层析，石油醚：乙酸乙酯＝15:1洗脱，得白色固体粉末46mg，收率72％。1H NMR(400MHz,CDCl3)δ9.47(s,1H,H-15),6.94(d,J＝4.1Hz,1H,H-13),6.03(d,J＝4.1Hz,1H,H-12),4.92(d,J＝15.6Hz,1H,H-11a),4.83(d,J＝15.6Hz,1H,H-11b),4.62(d,J＝14.0Hz,1H,H-3),4.44(dd,J＝8.9,5.2Hz,1H,H-8a),4.25(dt,J＝9.6,6.0Hz,1H,H-8b),4.07(d,J＝14.0Hz,1H,H-4),3.80–3.64(m,2H,H-2a,2b),2.37(dd,J＝15.4,3.3Hz,1H,H-5a),2.11(dd,J＝15.4,5.3Hz,1H,H-5b),1.57(s,3H,H-20),1.40(s,3H,H-21).13C NMR(100MHz,CDCl3)δ178.77(s),134.34(s),131.06(s),124.13(s),109.40(s),104.77(s),93.01(s),70.37(s),69.39(s),60.24(s),58.08(s),52.05(s),34.06(s),28.26(s),25.80(s).HRMS(ESI)calcd for C15H19NO5[M+H]+294.1331,found 294.1297.化合物XII的制备合成步骤参照化合物X的合成方法，收率78％。1H NMR(400MHz,CDCl3)δ9.48(s,1H,H-15),6.92(d,J＝3.6Hz,1H,H-13),6.01(d,J＝3.6Hz,1H,H-12),4.93–4.78(m,3H,H-11a,11b,H-3),4.56(dd,J＝11.6,5.7Hz,1H,H-8a),4.21(d,J＝6.1Hz,1H,H-8b),4.04(d,J＝14.1Hz,1H,H-4),3.97(d,J＝13.2Hz,1H,H-2a),3.85(d,J＝12.2Hz,1H,H-2b),2.14–2.00(m,2H,H-5a,5b),1.56(s,3H,H-20),1.38(s,3H,H-21).13CNMR(100MHz,CDCl3)δ178.68(s),134.24(s),131.16(s),123.83(s),109.08(s),104.65(s),94.45(s),71.62(s),69.27(s),61.73(s),58.03(s),53.46(s),34.83(s),27.23(s),25.54(s).HRMS(ESI)calcd for C15H19NO5[M+H]+294.1332,found 294.1297.
Pollenopyrroside A的制备：称取化合物X(50mg,0.17mmol)溶于30mL80％乙酸中，置于100mL茄形瓶中，30℃搅拌反应3.5h，TCL(甲醇：乙酸乙酯＝5：1)检测原料消失，停止反应，加入甲苯旋转蒸发带出乙酸，残余物硅胶柱层析，二氯甲烷：甲醇＝10：1洗脱，得Pollenopyrroside A42mg，收率85％。1H NMR(400MHz,CDCl3)δ9.46(s,1H,H-15),6.92(d,J＝4.1Hz,1H,H-13),6.03(d,J＝4.1Hz,1H,H-12),4.93–4.82(m,2H,H-11a,11b),4.58(d,J＝14.2Hz,1H,H-3),4.07(d,J＝14.3Hz,2H,H-8a,8b),3.80–3.69(m,2H,H-2a,2b),3.64–3.55(m,1H,H-4),2.30(dd,J＝14.8,3.1Hz,1H,H-5a),2.00(dd,J＝14.8,3.4Hz,1H,H-5b).13CNMR(100MHz,CDCl3)δ178.92(s),133.30(s),131.21(s),123.99(s),105.02(s),94.56(s),67.03(s),65.70(s),60.18(s),57.88(s),51.55(s),37.46(s).
Shensongine A的制备合成步骤参照Pollenopyrroside A的合成方法，收率81％。1HNMR(400MHz,CDCl3)δ9.45(s,1H,H-15),6.92(d,J＝3.7Hz,1H,H-13),6.01(d,J＝3.7Hz,1H,H-12),4.85–4.74(m,2H,H-11a,11b),4.70(d,J＝14.0Hz,1H,H-3),4.20–4.13(m,1H,H-8a),4.02(d,J＝14.1Hz,1H,H-8b),3.89(d,J＝2.9Hz,2H,H-2a,2b),3.81(d,J＝12.4Hz,1H,H-4),2.05(dd,J＝12.9,5.2Hz,1H,H-5a),1.96–1.88(m,1H,H-5b).
人宫颈癌HeLa细胞中缺氧诱导的HIF-1抑制活性的评价：将以慢病毒颗粒为载体共转染有HRE-Luc和CMV-Luc报告基因的Hela细胞复苏后培养于DMEM培养基中，其中含10％FBS和0.2μg/ml Puromycin。将对数生长期的细胞Trypsin(0.25％)消化后，吹打成单细胞悬液，接种于96孔培养板2×105cell/ml，在20％O2的培养箱中，37℃下培养12h。待细胞贴壁后，加入梯度浓度的受试化合物在常氧培养箱中培养1h，转至缺氧条件的三气培养箱中(1％O2、95％N2和5％CO2)37℃下培养。12h后裂解细胞，利用酶标仪先后检测各孔的HRE-Luc和CMV-Luc值，计算HRE-Luc相对荧光素酶值，按下列公式计算HIF-1抑制率:
抑制率(％)＝(对照-给药)/对照×100％
用Bliss法求出候选化合物的HIF-1半数抑制浓度IC50，单位μM。
单线态氧清除活性实验：将100μM的药物缓冲溶液(Tris-HCl)与ATTA-Eu3+探针(终浓度为10μM)结合后分别超声(频率0.5MHz；强度2w/cm2；距离6.5cm；连续发声)0min、5min、10min、15min、20min、25min后，取10μL溶液稀释100倍加入96孔板，每孔200μL，每组4个复孔。使用Perkin Elmer Victor1420型时间分辨荧光测定仪测定其荧光强度的改变。对照组为不含药物的缓冲溶液体系。
计算各组对单线态氧的清除率，采用公式：清除率＝1-AX/A0，其中Ax为加入生物碱的组分单线态氧产率，A0为对照组的单线态氧产率。
根据测定的荧光强度做图(附图1)可以看出生物碱Pollenopyrroside A和化合物VII均具有一定程度的清除单线态氧能力。计算化合物对单线态氧的清除率。由于空白组25min单线态氧产率有所下降，推测是水溶液中溶解的氧气消耗完全，继续超声基本没有单线态氧的产生，所以只计算5min～20min时各化合物对单线态氧的清除率。根据附图2可比较两种生物碱的清除率随时间变化的规律，在10min～15min达到稳定状态，15min～20min略有提高。对比Pollenopyrroside A和化合物VII可以看到，化合物VII比生物碱PollenopyrrosideA的清除单线态氧能力略强，可能由于其糖环部分多一个羟基。一般情况下，羟基越多，清除单线态氧能力越强。
Claims (2)
1.一种吡喃糖环吡咯螺缩酮生物碱的全合成方法，其特征在于，合成路线如下：
具体步骤如下：
(1)以D-葡糖为原料，有机酸提供酸性条件，50～80℃，反应时间2～5h，与二苄胺进行Amadori重排反应，得到化合物I；
(2)无机酸或H型阳离子交换树脂提供酸性条件，丙酮作为溶剂，反应温度为-10～25℃，反应时间为2～5h，化合物I的羟基用异丙叉基保护，得到化合物II；
(3)以钯碳为催化剂，反应温度为10～35℃，反应时间为6～24h，化合物II的苄基进行加氢还原，得到化合物III；
(4)在酸性条件下，化合物III与
进行Maillard缩合反应，得到化合物IV：酸性条件由质子酸或路易斯酸提供，反应温度为15℃～100℃，反应时间为8～24h；
(5)化合物IV在酸性条件下螺环化得到化合物V和化合物VI，酸性试剂选择对甲苯磺酸、氨基磺酸或樟脑磺酸，溶剂为二氯甲烷，反应温度为-10～10℃，反应时间为2～5h；
(6)化合物V或化合物VI脱除异丙叉基保护，得到Pollenopyrroside A或ShensongineA的类似物化合物VII和化合物VIII，采用下述一种方法：
(A)30％～80％乙酸既作为催化剂，又作为溶剂，反应温度为10～30℃，反应时间为2～6h；
(B)盐酸作为催化剂，甲醇或乙醇作为溶剂，反应温度为-10～10℃，反应时间为2～6h；
(7)化合物V或化合物VI裸露的羟基通过Barton-McCombie反应脱除，得到化合物IX或化合物XI，该反应的催化剂为咪唑，溶剂为四氢呋喃，化合物V或化合物VI与氢化钠、二硫化碳和碘甲烷反应成黄原酸酯，反应温度为10～35℃，反应时间为0.5～6h，分离纯化得化合物IX或化合物XI，在二氧六环为溶剂，过氧化苯甲酰为自由基引发剂，三乙基硅烷作用下脱除黄原酸酯，得到化合物X或化合物XII，反应温度为80～101℃，反应时间为0.5～6h；
化合物X或化合物XII在酸性条件下脱除异丙叉基保护基，得到最终产物Pollenopyrroside A或Shensongine A：采用下述一种方法：
(C)30％～80％乙酸既作为催化剂，又作为溶剂，反应温度为10～30℃，反应时间为2～6h；
(D)盐酸作为催化剂，甲醇或乙醇作为溶剂，反应温度为-10～10℃，反应时间为2～6h；
2.根据权利要求1所述的全合成方法，其特征在于，
步骤(1)中的有机酸为乙酸；
步骤(2)中的无机酸为盐酸或硫酸，阳离子交换树脂为A-15树脂；
步骤(3)中的溶剂为甲醇或乙醇；
步骤(4)中的质子酸为乙酸，路易斯酸为氯化锌或醋酸锌。
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| CN108997448A (zh) | 2018-12-14 |
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