本发明属于药物学领域，具体地涉及一种皂苷衍生物及其药物组合物和应用。
背景技术：
肿瘤作为人类健康的一大威胁一直受到广泛的关注，寻找新的抗肿瘤药物是全世界药物化学家研究的重点和热点。从天然产物(naturalproducts)中寻找新的抗肿瘤药物是抗肿瘤药物发现的主要途径之一。三萜皂苷是由三萜皂苷元与糖、糖醛酸等连接而成的天然产物，苷键类型多为与c-3位或其他位置羟基形成醚苷和与28位羧基形成的酯苷。现代研究发现，来源于100多种植物的至少150种天然三萜皂苷类成分具备潜在的抗肿瘤活性。
在众多的具有潜在抗肿瘤活性的三萜皂苷中，α-常春藤皂苷是其中的典型代表。α-常春藤皂苷是存在于多种植物中的一种五环三萜皂苷，3-氧原子上连着一个独特的二糖链，即：3-o-α-l-吡喃鼠李糖基-(1→2)-α-l-吡喃阿拉伯糖。文献报道α-常春藤皂苷在高于3μm时诱导p388细胞凋亡，并产生时间、剂量依赖性。kumaras.s.报道，以llc移植bdf1小鼠为模型，以10mg/kg/d的剂量腹腔注射psa给药，连续给药7天，第8天的抑瘤率是65％，第15天的抑瘤率是71％(planta.med.,2001,67:29-32)。但是文献报道，α-常春藤皂苷具有强烈的溶血性，引起50％红细胞溶解的浓度(hd50)是10μm(bioorg.med.chem.2009,17,2002-2008)。我们前期的研究结果与上述文献报道吻合。α-常春藤皂苷虽然在肿瘤动物模型上显示出明确的抗肿瘤活性，但是其强烈的溶血性阻止其在临床上的应用。gauthierc.于2009年撰文指出，“皂苷类化合物对大多数动物，包括人，因溶血诱发的毒性是阻碍其作为临床抗肿瘤剂的主要绊脚石”(bioorg.med.chem.2009,17,2002-2008)。因此，解决皂苷类化合物的溶血性问题显得尤为迫切。
截止目前为止，皂苷类化合物导致溶血的机制并不清楚。有学者认为，皂苷与红细胞的细胞膜接触后，与胆甾醇结合形成不溶性的复合物，在细胞膜上形成空洞，增加了细胞膜的通透性，引起红细胞内的血红蛋白外流导致溶血现象。而winter却认为皂苷与水通道蛋白相互作用，使红细胞内水的转运增加，诱发溶血。但并不是所有的皂苷都具有溶血作用，如以原人参三醇和齐墩果酸为苷元的人参皂苷有显著的溶血作用，而以原人参二醇为苷元的人参皂苷却有抗溶血作用，因此人参总皂苷并不表现出溶血现象。皂苷的溶血活性还和糖链部分有关，单糖链皂苷的溶血作用明显，某些双糖链皂苷无溶血作用，但经过部分水解成为单糖链皂苷后就具有溶血作用。
chwalekm.对19个常春藤二糖苷的溶血性及细胞毒性的研究表明：1)糖链对细胞毒性、溶血性有重要的影响，包括端基碳的构型、糖基取代的位置、糖的种类；2)28-cooh成甲酯后，溶血性增强，细胞毒性下降，可能是甲酯化产物增加了苷元部分的脂溶性，进而改变了皂苷与细胞膜的结合方式；3)28-cooh对细胞毒性有重要影响；4)端基碳的构型为α-l或β-d型(天然构型)，有利于提高皂苷的溶血性、细胞毒性；5)α-l-rhap-(1→2)-α-l-arap对于齐墩果酸皂苷或常春藤皂苷的细胞毒性而言是一个优秀的片段(biochi.biophy.acta.2006,1760,1418-1427)。
综上所述，苷元与糖链等诸多因素的参与，造成了α-常春藤皂苷的溶血性，而皂苷的表面活性是由皂苷特殊的分子结构决定的；换言之，皂苷的溶血性与皂苷的表面活性之间并无必然联系。因此解决皂苷的溶血性问题并不是一个不可逾越的鸿沟。我们以α-常春藤皂苷为先导物，设计合成多个皂苷衍生物，进行体外的抗肿瘤活性研究，重点关注衍生物的溶血性，本专利旨在提高或保持α-常春藤皂苷抗肿瘤活性的同时消除或大幅降低溶血毒性。
技术实现要素：
本发明的目的是针对上述缺陷，提供一种具有抗肿瘤活性且能够消除或大幅降低溶血性的皂苷衍生物。
为实现上述目的，本发明采用的技术方案是：
根据本发明的第一方面，提供一种皂苷衍生物，该皂苷衍生物为具有结构通式(i)的化合物或其可药用盐，
式(i)中，
x为c＝o、c＝n-oh、ch-oh，y为c或ch；或x-y为ch＝ch；
z为ch2或c＝o；
r1为羟基、葡萄糖基、鼠李糖基、阿拉伯糖基、木糖基、核糖基、甘露糖基、半乳糖基或果糖基；
r2为cor3，r3为羟基、烷氧基、芳香氧基、杂芳香氧基、寡糖基、脂肪胺基、环状脂肪胺基、芳香胺基、杂芳香胺基、氨基酸、氨基寡糖或no供体；或r2与y之间通过共价键连接构成酯。
进一步地，式(i)中，x为c＝o或c＝n-oh，y为ch，z为ch2，r2为cor3，r3为羟基、烷氧基、芳香氧基、杂芳香氧基、寡糖基、脂肪胺基、环状脂肪胺基、芳香胺基、杂芳香胺基、氨基酸、氨基寡糖或no供体。
具体地，r2为cooh。
进一步地，x-y为ch＝ch，z为c＝o，r2为cor3，r3为羟基、烷氧基、芳香氧基、杂芳香氧基、寡糖基、脂肪胺基、环状脂肪胺基、芳香胺基、杂芳香胺基、氨基酸、氨基寡糖或no供体。
进一步地，x-y为ch＝ch，z为ch2，r2为cor3，r3为氨基酸或no供体。
进一步地，上述no供体为烷氧基硝酸酯。
具体地，烷氧基硝酸酯的碳数为1、2、3、4、5、6、7、8、9、10、11或12。
进一步地，上述氨基酸为-nh(ch2)ncooh或-nh(ch2)mconh(ch2)pcooh，其中n为1-8之间的整数，m、p独立地为1-4之间的整数。
进一步地，x为c＝o、ch-oh或c＝n-oh，y为c，r2与y之间通过共价键连接形成酯。
具体地，r2为-coo-。
进一步地，皂苷衍生物为如下化合物中的一种或多种的组合：
根据本发明，所述的结构通式(i)的化合物，其不仅包括单一的某种化合物形式，还包括多种结构满足通式(i)要求的化合物的混合物形式，以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。所述的可药用盐包括但不限于盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、苯酸盐、甲基苯磺酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐等。
根据本发明的第二方面，提供一种用于如上所述的皂苷衍生物的中间体，该中间体为：
根据本发明的第三方面，提供一种用于抗肿瘤的药物组合物，该药物组合物包含本发明上述的皂苷衍生物。
进一步地，皂苷衍生物在所述药物组合物中作为活性成分使用。
上述药物组合物的活性成分可以仅包含上述的皂苷衍生物，此时，皂苷衍生物在药物组合物中含量优选为有效量的；或者活性成分还可以为上述皂苷衍生物与其他抗肿瘤活性成分的组合。
根据本发明的第四方面，提供根据以上所述的皂苷衍生物在制备抗肿瘤药物组合物中的应用。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
与α-常春藤皂苷相比，本发明的皂苷衍生物不仅具有较强的抗肿瘤活性，而且溶血毒性大大降低。
具体实施方式
本发明述及的结构通式(i)的化合物可利用本领域常规的化学反应来制备，根据具体的目标化合物结构，可相应设计合成路线。举例如下：
流程一，如下合成路线所示：
以化合物1或2在极性溶剂中，以乙酸酐为酰化剂，制得化合物3或4，后用重铬酸钾处理得到化合物5或6，后水解得到化合物7或8；
以化合物3或4为原料，在间氯过氧苯甲酸的作用下得到化合物9或10，后水解得到化合物11或12；
以化合物3或4为原料，与溴化苄反应制得化合物15或16，在氢气环境下用金属催化剂催化制得化合物17或18，后水解得到化合物19或20；
以化合物17或18为原料，在非极性溶剂下与二氯二氰基苯醌反应制得化合物21或22，后水解得到化合物23或24；
以化合物15为原料，与盐酸羟胺反应得到化合物25，在氢气环境下用金属催化剂催化制得化合物26，后水解得到化合物27。
流程二，如下合成路线所示：
以化合物5、6或17为原料，与草酰氯反应制得化合物28、29或32，直接与甘氨酸乙酯盐酸盐反应得到酰胺中间体，后水解得到化合物30、31或33。
流程三，如下合成路线所示：
以化合物3为原料，与草酰氯反应制得化合物34，直接与氨基酸乙酯盐酸盐或甘氨酰甘氨酸乙酯盐酸盐反应得到酰胺中间体，后水解得到化合物35-38；
流程四：如下合成路线所示：
以化合物1为原料，在极性溶剂和弱碱环境中，与溴代烷烃反应得到化合物39-41，处理后直接与硝酸银反应制得化合物42-44。
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。
本发明的实施例中，熔点用x-4熔点仪测定；1h-nmr与13c-nmr用varianmercury400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未作特别说明时均为200-300目，洗脱液的配比均为体积比。
实施例1：制备11-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-28-酸(化合物7)
步骤1-1：制备化合物3
原料α-常春藤皂苷(化合物1)(5.00g,6.66mmol)溶于无水吡啶(20ml)中，搅拌下加入乙酸酐(6.0ml,62.7mmol)，室温下搅拌12h。反应结束，加入100ml乙酸乙酯，用10％hcl调节ph4-5；有机层用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩出去溶剂，硅胶柱层析(石油醚：乙酸乙酯＝2:1)，得白色固体6.02g，即化合物3，产率90.0％。
所得白色固体的熔点(mp)为169–170℃。所得白色固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.21(s,1h,h-1”),4.91–5.03(m,2h,h-1’,h-12),4.42(d,j＝6.4hz,1h),4.04–4.20(m,3h),3.90(ddd,j＝23.9,14.0,5.0hz,3h),3.55(dd,j＝16.7,8.7hz,2h),2.80(d,j＝13.5hz,1h),2.13(s,3h,ch3co),2.10(s,3h,ch3co),2.09(s,3h,ch3co),2.05(s,3h,ch3co),2.03(s,3h,ch3co),1.96(s,3h,ch3co),1.25(t,j＝7.1hz,3h),1.20(d,j＝6.2hz,3h),1.09(s,3h),0.93(s,3h),0.91(s,3h),0.89(s,3h),0.78(s,3h),0.73(s,3h)；
13cnmr(100mhz,cdcl3,δ):183.48(c-28),170.57(ch3co),170.53(ch3co),170.45(ch3co),170.30(ch3co),170.19(ch3co),169.80(ch3co),143.73(c-13),122.59(c-12),103.68(c-1’),98.37(c-1”),82.10(c-3),77.36,74.55,71.98,71.10,69.65,68.71,67.94,67.28,65.18,62.80,60.55,47.94,46.64,45.89,42.03,41.66,41.16,39.37,38.44,36.67,33.89,33.19,32.53,32.47,30.80,27.64,25.88,25.62,23.69,23.51,22.95,21.19,21.17(ch3co),21.12(ch3co),21.07(ch3co),20.95(ch3co),20.92(ch3co),20.79(ch3co),18.08,17.47,17.06,15.95,14.32,12.74。
步骤1-2：制备化合物5
取化合物3(600mg,0.6mmol)溶于冰乙酸(20ml)，加入重铬酸钾(352mg,1.2mmol)，加冷凝装置于100℃油浴锅中回流，薄层硅胶色谱检测反应进度，待原料大部分消失后停止反应。反应结束后，冷却至室温，过滤除去固体，旋转蒸发仪下除去大量冰乙酸，加乙酸乙酯(50ml)稀释，5％氢氧化钠溶液(30ml×2)洗去多余冰乙酸，饱和食盐水(30ml×3)洗涤有机层，无水硫酸钠干燥，硅胶柱层析(石油醚：乙酸乙酯＝2:1)，得黄色固体503mg，即化合物5，产率83％。
所得固体的熔点(mp)为189–190℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.26(s,1h,h-1”),5.22(d,j＝3.2hz,1h,h-12),5.16–5.20(m,1h,h-1’),5.02(dt,j＝14.4,7.1hz,3h),4.94(dd,j＝9.0,3.4hz,1h),4.38(d,j＝6.5hz,1h),4.04–4.15(m,4h),3.88–3.97(m,3h),3.84(dd,j＝8.9,6.6hz,2h),3.48–3.60(m,2h),2.11(s,3h),2.08(s,3h),2.08(s,3h),2.02(s,3h),2.00(s,3h),1.94(s,3h),1.19(d,j＝6.2hz,3h),1.12(s,3h),1.08(s,3h),1.02(s,3h),0.94(s,3h),0.90(s,3h),0.79(s,3h)；
13cnmr(75mhz,cdcl3,δ):200.24(c-11),182.43(c-28),170.53(ch3co),170.53(ch3co),170.48(ch3co),170.28(ch3co),170.17(ch3co),169.79(ch3co),168.52(c-12),128.05(c-13),103.69(c-1’),98.28(c-1”),81.77(c-3),77.36,74.39,72.07,71.11,69.65,68.66,67.94,67.25,65.20,62.92,61.96,60.55,47.83,46.04,45.09,44.22,43.50,42.36,41.51,39.07,36.91,33.74,32.96,32.70,31.64,30.78,27.71,25.64,23.49,22.75,21.19(ch3co),21.12(ch3co),21.07(ch3co),20.93(ch3co),20.79(ch3co),19.08(ch3co),17.46,17.18,16.78,14.32,12.74；
hrms-esi(m/z)[m-h]-:calcd.forc53h75o191015.4903,found1015.5057。
步骤1-3：制备化合物7
将化合物5(503mg,0.495mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)溶液，加入氢氧化钾(332mg,5.93mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得黄色固体317mg，即化合物7，产率83.6％。
所得固体的熔点(mp)为212–213℃。所得固体的核磁数据为：
1hnmr(400mhz,pyridine-d5,δ):6.28(s,1h,h-1”),5.97(s,1h,h-12),5.10(d,j＝6.3hz,1h,h-1’),4.75(d,j＝1.8hz,1h),4.62–4.73(m,2h),4.53–4.61(m,1h),4.30(ddd,j＝16.8,7.9,4.2hz,2h),4.14–4.25(m,2h),4.10(dd,j＝7.9,3.5hz,1h),3.76(d,j＝10.7hz,1h),3.68(d,j＝10.3hz,1h),3.29(t,j＝13.4hz,1h),2.63(s,1h),1.63(d,j＝6.2hz,3h),1.36(s,3h),1.35(s,3h),1.19(s,3h),1.10(s,3h),0.91(s,3h),0.91(s,3h)；
13cnmr(100mhz,pyridine-d5,δ):200.44(c-11),180.05(c-28),170.05(c-12),128.53(c-13),104.87(c-1’),102.03(c-1”),81.36(c-3),76.19,75.25,74.48,72.91,72.71,70.04,69.80,66.19,64.27,62.71,50.03,48.00,46.49,45.71,44.84,44.35,44.29,42.68,40.23,37.77,34.33,33.24,32.59,31.17,30.32,28.73,26.70,23.93,23.77,19.80,18.90,17.58,17.50,14.35；
hrms-esi(m/z)[m+na]+:calcd.forc41h64o13na787.4245,found787.4239。
实施例2：制备11-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)[β-d-吡喃葡萄糖-(1→4)]-α-l-吡喃阿拉伯糖齐墩果烷-28-酸(化合物8)
步骤2-1：制备化合物4
原料化合物2(6.08g,6.66mmol)溶于无水吡啶(20ml)中，搅拌下加入乙酸酐(8.6ml,89.91mmol)，室温下搅拌12h。反应结束，加入100ml乙酸乙酯，用10％hcl调节ph4-5；有机层用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩出去溶剂，硅胶柱层析(石油醚：乙酸乙酯＝2:1)，得白色固体7.40g，即化合物4，产率86％。
所得固体的熔点(mp)为172–173℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.26(d,j＝7.1hz,1h,h-1”),5.12–5.22(m,1h,h-12),5.05(s,1h,h-1’),4.96(d,j＝8.5hz,1h,h-1”’),4.91(s,2h),4.53(dd,j＝16.1,7.5hz,1h),4.25(d,j＝13.7hz,2h),4.13(dd,j＝19.6,10.0hz,3h),4.02(s,4h),3.68–3.84(m,4h),3.58(s,1h),3.43(d,j＝27.1hz,1h),2.80(dd,j＝16.5,8.8hz,1h),2.14(s,3h,ch3co),2.08(s,3h,ch3co),2.08(s,3h,ch3co),2.04(s,9h,ch3co),2.01(s,3h,ch3co),1.99(s,3h,ch3co),1.97(s,3h,ch3co),1.25(s,3h),1.18(d,j＝5.3hz,3h),1.10(s,3h),0.93(s,3h),0.92(s,3h),0.89(s,3h),0.74(s,3h)；
13cnmr(100mhz,cdcl3,δ):183.46(cooh),170.79(ch3co),170.68(ch3co),170.55(ch3co),170.30(ch3co),170.22(ch3co),170.10(ch3co),170.04(ch3co),169.57(ch3co),169.53(ch3co),143.67(c-13),122.63(c-12),101.53(c-1”’),101.31(c-1’),98.24(c-1”),82.03(c-3),77.36,74.72,72.71,71.88,71.06,70.96,69.57,68.99,68.44,67.29,65.39,61.92,60.53,47.96,47.90,46.63,45.97,45.94,42.03,41.79,41.68,41.13,39.38,38.30,36.68,33.18,32.49,30.78,29.81,25.88,23.68,21.17,21.11(ch3co),21.06(ch3co),21.01(ch3co),20.96(ch3co),20.93(ch3co),20.90(ch3co),20.87(ch3co),20.82,20.72(ch3co),20.69(ch3co),17.42,17.04,15.93,14.32,12.74.
步骤2-2:制备化合物6
取化合物4(775mg,0.6mmol)溶于冰乙酸(20ml)，加入重铬酸钾(352mg,12mmol)，加冷凝装置于100℃油浴锅中回流，薄层硅胶色谱检测反应进度，待原料大部分消失后停止反应。反应结束后，冷却至室温，过滤除去固体，旋转蒸发仪下除去大量冰乙酸，加乙酸乙酯(50ml)稀释，5％氢氧化钠溶液(30ml×2)洗去多余冰乙酸，饱和食盐水(30ml×3)洗涤有机层，无水硫酸钠干燥，硅胶柱层析(石油醚：乙酸乙酯＝2:1)，得黄色固体634mg，即化合物6，产率81％。
所得固体的熔点(mp)为168–169℃。所得固体的核磁数据为：
1hnmr(600mhz,cdcl3,δ):5.58(s,1h,h-1”),5.18(d,j＝13.2hz,1h,h-12),5.15–5.09(m,1h,h-1’),4.99(d,j＝10.6hz,2h),4.89–4.95(m,1h),4.87(s,1h),4.50(d,j＝7.4hz,1h),4.46(s,1h),4.20(d,j＝9.2hz,1h),4.11(d,j＝11.6hz,1h),4.06(d,j＝6.7hz,1h),3.98(s,2h),3.91(s,1h),3.80(d,j＝11.2hz,1h),3.71(s,1h),3.67(d,j＝6.8hz,1h),3.52(d,j＝5.0hz,1h),3.37(d,j＝7.0hz,1h),2.91(d,j＝11.2hz,1h),2.75(d,j＝12.0hz,1h),2.09(s,3h),2.04(s,6h),2.01(s,3h),1.99(s,3h),1.98(s,3h),1.96(s,3h),1.94(s,3h),1.92(s,3h),1.28(s,3h),1.14(s,3h),1.09(s,3h),0.88(s,3h),0.86(s,3h),0.72(s,3h)；
13cnmr(150mhz,cdcl3,δ):200.07(c-11),182.31(cooh),170.68(ch3co),170.57(ch3co),17040(ch3co)，17020(ch3co)，17008(ch3co)，16996(ch3co)，16993(ch3co)，16942(ch3co)169.38(ch3co),168.41(c-12),127.93(c-13),101.40(c-1”’),101.17(c-1’),98.17(c-1”),81.62,74.67,72.78,72.62,71.77,70.99,70.84,69.48,68.87,68.31,67.17,65.26,61.84,61.74,47.67,45.94,44.97,44.16,43.41,42.25,41.40,38.80,36.83,33.66,32.85,32.62,31.56,30.67,29.68,27.64,25.02,23.41,23.38,22.67,20.97,20.89,20.83,20.78,20.76,20.70,20.60,20.57,19.08,17.32,17.12,16.67,14.21,12.62；
hrms-esi(m/z)[m+h]+:calcd.forc65h93o271305.5904,found1305.5871。
步骤2-3：制备化合物8
将化合物6(646mg,0.495mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)溶液，加入氢氧化钾(332mg,5.93mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得黄色固体389mg，即化合物8，产率81％。
所得固体的熔点(mp)为223–224℃。所得固体的核磁数据为：
1hnmr(600mhz,pyridine-d5,δ):6.26(s,1h,h-1”),5.97(s,1h,h-12),5.11(d,j＝7.9hz,1h,h-1’),4.96(d,j＝6.7hz,1h,h-1”’),4.71(s,1h),4.63(d,j＝8.5hz,1h),4.03(d,j＝7.9hz,1h),3.88(s,1h),3.74(d,j＝10.4hz,1h),3.28(dd,j＝33.9,12.8hz,1h),2.62(s,1h,h-10),1.64(d,j＝5.5hz,3h,h-6”),1.37(s,3h),1.35(s,3h),1.27(s,3h),1.18(s,3h),1.12(s,3h),0.91(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):200.42(c-11),180.00(cooh),170.03(c-12),128.52(c-13),107.14(c-1”’),104.84(c-1’),102.03(c-1”),81.39(c-3),80.83,79.99,79.16,78.89,76.63,75.81,75.46,74.47,72.80,72.59,71.53,69.98,67.53,65.80,64.21,62.80,62.70,50.02,48.05,46.48,45.71,44.85,44.35,44.27,42.67,40.23,37.77,34.33,34.15,33.35,33.24,32.59,32.46,32.24,31.17,29.95,28.73,26.77,26.01,23.95,23.77,23.28,21.53,19.80,18.98,17.57,17.51；
hrms-esi(m/z)[m+na]+:calcd.forc47h74o18na949.4773,found949.4767。
实施例3：制备12，23-二羟基-3-o-α-l-吡喃鼠李糖-(1→2)[3,4-o-二乙酰基]-α-l-吡喃阿拉伯糖-齐墩果烷-28-γ-内酯(化合物11)
步骤3-1：制备化合物9
取化合物3(482mg，0.481mmol)溶于无水氯仿(15ml)，避光条件下加入间氯过氧苯甲酸(250mg，1.25mmol)，室温下避光搅拌24h。反应停止后，真空除去氯仿，得白色固体，加入乙酸乙酯50ml，用10％氢氧化钠溶液(30mlx2)，饱和食盐水(30mlx3)洗涤，无水硫酸钠干燥有机层，硅胶柱层析(石油醚：乙酸乙酯＝3:1)得白色固体376mg，即化合物9，产率约78％。
所得固体的熔点为167-168℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.24(d,j＝3.3hz,1h,h-1”),5.18–5.24(m,1h,h-12),5.03–5.07(m,1h,h-1’),4.96(dd,j＝9.0,3.4hz,1h),4.41(d,j＝6.5hz,1h),4.12(dd,j＝20.5,9.4hz,2h),3.90(t,j＝17.8hz,3h),3.57(d,j＝11.5hz,1h),2.13(s,3h),2.10(s,3h),2.09(s,3h),2.05(s,3h),2.02(s,3h),1.96(s,3h),1.28(s,3h),1.21(d,j＝6.2hz,3h),1.13(s,3h),0.97(s,3h),0.91(s,3h),0.89(s,3h),0.79(s,3h)；
13cnmr(100mhz,cdcl3,δ):179.98(c-28),170.51(ch3co),170.46(ch3co),170.44(ch3co),170.29(ch3co),170.16(ch3co),169.79(ch3co),103.78(c-1’),98.22(c-1”),90.59(c-13),81.89(c-3),77.36,76.46,74.26,72.12,71.13,69.69,68.68,68.03,67.24,65.15,63.02,60.55,51.19,47.97,44.89,44.81,42.40,42.15,42.10,39.52,38.79,36.20,34.23,33.76,33.40,31.70,28.97,28.08,27.57,25.71,24.03,21.27,21.20,21.13,21.08,20.95,20.92,20.81,18.74,18.69,17.56,17.46,16.92,14.34,12.60；
hrms-esi(m/z)[m-h]-:calcd.forc53h77o191017.5059,found1017.5172。
步骤3-2：制备化合物11
将化合物9(376mg,0.369mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)溶液，加入氢氧化钾(248mg,4.42mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得白色固体256mg，即化合物11，产率91％。
所得固体的熔点(mp)为206–207℃。所得固体的核磁数据为：
1hnmr(400mhz,pyridine-d5,δ):6.23(s,1h,h-1”),5.06(d,j＝6.1hz,1h,h-12),4.79(s,1h,h-1’),4.67(dd,j＝9.0,6.2hz,2h),4.48–4.59(m,1h),4.34(t,j＝9.4hz,1h),4.16(ddd,j＝24.3,17.0,7.5hz,6h),3.71(dd,j＝17.7,11.1hz,2h),1.61(d,j＝5.9hz,3h),1.54(s,3h),1.32(s,3h),1.04(s,3h),0.92(s,3h),0.86(s,3h),0.79(s,3h)；
13cnmr(100mhz,pyridine-d5,δ):180.05(c-28),104.72(c-1’),101.95(c-1”),91.80(c-13),81.31(c-3),76.04,76.01,75.14,74.40,72.84,72.67,69.98,69.75,66.10,64.19,51.97,49.98,48.06,45.36,45.26,43.93,42.98,42.95,39.76,39.43,36.67,34.78,34.42,33.54,31.92,29.67,28.68,28.57,26.58,24.10,22.02,19.36,19.03,18.86,17.99,17.51,14.02；
hrms-esi(m/z)[m+na]+:calcd.forc41h66o13na789.4401,found789.4260。
实施例4：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)[β-d-吡喃葡萄糖-(1→4)]-α-l-吡喃阿拉伯糖齐墩果烷-28-γ-内酯(化合物12)
步骤4-1：制备化合物10
取化合物4(621mg，0.481mmol)溶于无水氯仿(15ml)，避光条件下加入间氯过氧苯甲酸(250mg，1.25mmol)，室温下避光搅拌24h。反应停止后，真空除去氯仿，得白色固体，加入乙酸乙酯50ml，用10％氢氧化钠溶液(30mlx2)，饱和食盐水(30mlx3)洗涤，无水硫酸钠干燥有机层，硅胶柱层析(石油醚：乙酸乙酯＝3:1)得白色固体503mg，即化合物10，产率80％。
所得固体的熔点为155-156℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.23(s,1h,h-1”),5.21(s,1h,h-12),5.16(d,j＝9.5hz,h-1’),4.99–5.08(m,3h),4.90–4.99(m,3h),4.54(d,j＝7.9hz,1h),4.50(d,j＝3.4hz,1h),4.25(dd,j＝12.3,4.6hz,1h),4.12(dt,j＝14.3,4.3hz,4h),4.02(t,j＝6.3hz,1h),3.82–3.91(m,1h),3.68–3.78(m,2h),3.55(q,j＝6.9hz,1h),3.43(dd,j＝11.7,4.4hz,1h),2.14(s,3h),2.08(s,3h),2.08(s,3h)2.04(s,3h),2.03(s,3h),2.03(s,3h),2.01(s,3h),1.98(s,3h),1.97(s,3h),1.28(s,3h),1.25(s,3h),1.13(s,3h),0.96(s,3h),0.91(s,3h),0.89(s,3h),0.75(s,3h)；
13cnmr(100mhz,cdcl3,δ):179.97(c-28),170.78(ch3co),170.68(ch3co),170.51(ch3co),170.30(ch3co),170.23(ch3co),170.10(ch3co),170.05(ch3co),169.57(ch3co),169.56(ch3co),101.57(c-1”’),101.44(c-1’),98.20(c-1”),90.59(c-13),81.81(c-3),77.36,76.44,74.63,72.99,72.67,71.88,71.12,70.96,69.59,68.97,68.44,67.27,65.34,61.93,60.53,51.18,47.93,44.91,44.80,42.39,42.14,42.09,39.52,38.62,36.12,34.23,33.77,33.38,31.68,29.81,28.98,28.08,27.57,25.22,24.02,21.27,21.17,21.03,21.02,20.95,20.91,20.88,20.83,20.72,20.70,18.71,17.59,17.41,16.88,14.32,12.53；
hrms-esi(m/z)[m+na]+:calcd.forc65h94o27na1329.5881,found1329.5496。
步骤4-2：制备化合物12
将化合物10(482mg,0.369mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)溶液，加入氢氧化钾(248mg,4.42mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得白色固体308mg，即化合物12，产率90％。
所得固体的熔点(mp)为198–199℃。所得固体的核磁数据为：
1hnmr(400mhz,cd3od,δ):5.15(s,1h,h-1”),4.46(d,j＝5.9hz,1h,h-1’),4.44(dd,j＝17.2,6.8hz,3h),4.41(d,j＝7.6hz,1h,h-10),4.08(dd,j＝12.1,3.5hz,1h),1.29(s,3h),1.18(d,j＝6.0hz,3h,h-6”),1.18(d,j＝6.0hz,6h),1.05(s,3h),0.91(s,3h),0.86(s,3h),0.86(s,3h),0.63(s,3h)；
13cnmr(75mhz,cd3od,δ):182.57(c-28),105.86(c-1”’),104.45(c-1’),101.77(c-1”),93.29(c-13),82.17(c-3),79.54(c-12),77.90,77.70,76.78,76.47,75.21,73.81,71.94,71.86,71.20,70.07,64.92,64.46,62.46,52.35,46.12,45.62,44.03,43.32,43.24,40.15,39.70,37.04,35.12,34.47,33.68,32.34,29.53,28.92,28.63,26.56,24.20,22.28,20.92,19.18,19.02,18.20,17.95,17.32,13.56；
hrms-esi(m/z)[m+cl]-:calcd.forc47h76o18cl963.4721,found963.4853。
实施例5：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-28-酸(化合物19)
步骤5-1：制备化合物13
取化合物3(2g，1.99mmol)和无水碳酸钾(827mg，5.99mmol)置于反应瓶中，加入n,n-二甲基甲酰胺(20ml)，边搅拌边滴加溴化苄(0.5ml)，室温下搅拌6小时。反应结束后，加水(100ml)稀释反应体系，得白色乳浊液，用乙酸乙酯(50mlx3)萃取，合并有机层饱和食盐水(50mlx3)洗涤，无水硫酸钠干燥有机层，柱层析硅胶(石油醚：乙酸乙酯＝4:1)得白色固体1.98g，即化合物13，产率92％。
所得固体熔点为168-169℃。所得固体的核磁数据如下：
1hnmr(400mhz,cdcl3,δ):7.19–7.32(m,5h,ar-),5.09–5.27(m,5h),4.93–5.06(m,5h),4.90(d,j＝8.7hz,1h，h-1’),4.35(d,j＝6.2hz,1h),4.06(t,j＝10.0hz,3h),3.74–3.94(m,4h),3.50(t,j＝10.4hz,2h),2.80(t,j＝17.1hz,1h),2.06(s,3h,ch3co),2.03(s,3h,ch3co),2.02(s,3h,ch3co),1.98(s,3h,ch3co),1.96(s,3h,ch3co),1.89(s,3h,ch3co),1.14(d,j＝6.1hz,3h),1.02(s,3h),0.84(s,6h),0.82(s,3h),0.72(s,3h),0.52(s,3h)；
13cnmr(75mhz,cdcl3,δ):177.48(c-28),170.48(ch3co),170.46(ch3co),170.37(ch3co),170.23(ch3co),170.12(ch3co),169.71(ch3co),143.86(c-13),136.49(ar-c),128.49(ar-c),128.06(ar-c),128.00(ar-c),122.43(c-12),103.70(c-1’),98.20(c-1”),82.02(c-3),74.29,72.07,71.08,69.63,68.65,67.97,67.19,66.00,65.15,62.94,47.89,46.79,45.90,41.98,41.66,41.45,39.34,38.42,36.60,33.91,33.20,32.42,30.78,29.78,27.59,25.80,25.63,23.74,23.48,23.06,21.12,21.08,21.04,20.90,20.87,20.76,18.05,17.41,16.97,15.90,12.78；
hrms-esi(m/z)[m+h]+:calcd.forc60h85o181093.5736,found1093.5579。
步骤5-2：制备化合物15
取化合物13(800mg，0.732mmol)溶于无水氯仿(20ml)，避光条件下加入75％间氯过氧苯甲酸(337mg，1.25mmol)，室温下避光搅拌24h。反应停止后，真空除去氯仿，得白色固体，加入乙酸乙酯50ml，用10％氢氧化钠溶液(30ml×2)，饱和食盐水(30ml×3)洗涤，无水硫酸钠干燥有机层，硅胶柱层析(石油醚：乙酸乙酯＝3:1)得白色固体707mg，即化合物15，产率约87％。
所得固体的熔点为154-155℃。
所得固体的核磁数据如下：
1hnmr(400mhz,cdcl3,δ):7.15–7.31(m,5h,ar-h),5.17(d,j＝2.9hz,2h),5.14(s,2h),4.97(dd,j＝16.9,7.8hz,3h),4.88(dd,j＝8.9,3.2hz,1h),4.31(d,j＝6.6hz,1h),3.99–4.08(m,2h),3.85(d,j＝11.9hz,2h),3.78(dd,j＝8.6,7.0hz,1h),3.39–3.55(m,2h),2.74(d,j＝14.3hz,1h),2.37(d,j＝3.8hz,1h),2.06(s,3h,ch3co),2.03(s,3h,ch3co),2.02(s,3h,ch3co),1.98(s,3h,ch3co),1.96(s,3h,ch3co),1.89(s,3h,ch3co),1.14(d,j＝6.1hz,3h),0.91(s,3h),0.82(s,3h),0.79(s,3h),0.75(s,3h),0.72(s,3h),0.52(s,3h)；
13cnmr(75mhz,cdcl3,δ):211.62(c-12),177.43(c-28),170.42(ch3co),170.38(ch3co),170.29(ch3co),170.16(ch3co),170.03(ch3co),169.66(ch3co),136.31(c-13),128.54(ar-c),128.43(ar-c),128.18(c-12),103.66(c-1’),98.17(c-1”),81.48(c-3),74.29,72.01,70.99,69.53,68.54,67.88,67.14,65.96,64.97,63.01,60.41,51.81,49.86,47.78,47.17,41.87,41.11,38.44,37.79,36.42,36.23,34.43,33.42,32.80,32.02,31.45,30.66,29.69,27.30,25.41,23.21,22.66,21.06(ch3co),20.96(ch3co),20.83(ch3co),20.80(ch3co),20.68(ch3co),20.56(ch3co),17.91,17.34,15.65,14.22,12.46；
hrms-esi(m/z)[m+na]+:calcd.forc60h84o19na1131.5505；found:1131.5093。
步骤5-3：制备化合物17
取化合物15(707mg，0.638mmol)溶于无水四氢呋喃(15ml)，加入10％钯碳(50mg)至于氢气环境下搅拌4小时。反应结束后，过滤除去钯碳，柱层析硅胶(石油醚：乙酸乙酯＝5:1)得白色固体620mg，即化合物17，产率97％。
所得固体的熔点为183-184℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.25(s,1h,h-1”),5.21(s,1h,h-12),5.00–5.08(m,2h),4.96(dd,j＝9.0,3.4hz,1h,h-1’),4.39(d,j＝6.6hz,1h),4.07–4.17(m,1h),3.93(d,j＝12.2hz,2h),3.86(dd,j＝8.9,6.7hz,1h),3.55(dd,j＝19.6,7.9hz,2h),2.75(d,j＝10.1hz,1h),2.67(s,1h),2.13(s,3h),2.10(s,6h),2.05(s,3h),2.03(s,3h),1.96(s,3h),1.21(d,j＝6.2hz,3h),0.98(s,3h),0.97(s,3h),0.91(s,3h),0.90(s,3h),0.89(s,3h),0.79(s,3h)；
13cnmr(100mhz,cdcl3,δ):211.40(c-12),182.71(c-28),170.43(ch3co),170.41(ch3co),170.31(ch3co),170.18(ch3co),170.05(ch3co),169.67(ch3co),103.66(c-1’),98.25(c-1”),81.49(c-3),74.48,71.90,70.98,69.55,68.60,67.84,67.18,64.95,62.92,60.45,51.88,49.91,47.80,47.09,46.99,41.90,41.24,38.51,37.80,36.50,36.09,34.41,33.35,33.02,31.84,31.53,30.62,29.71,27.47,25.40,23.10,22.56,21.06,20.99,20.95,20.83,20.79,20.67,20.54,17.95,17.35,16.20,15.70,12.42；
hrms-esi(m/z)[m+h]+:calcd.forc53h79o191019.5216；found:1019.4854。
步骤5-4：制备化合物19
将化合物17(310mg,0.304mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)，加入氢氧化钾(205mg,3.65mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)得白色固体220mg，即化合物19，产率94％。
所得固体的熔点221-222℃。所得固体的核磁数据如下：
1hnmr(400mhz,pyridine-d5,δ):6.26(s,1h,h-1”),5.06(d,j＝6.3hz,1h,h-1’),4.81(s,1h),4.68(d,j＝8.9hz,1h),4.49–4.62(m,1h),4.35(t,j＝9.4hz,1h),4.26(dd,j＝11.9,3.7hz,1h),4.06–4.23(m,2h),3.68(t,j＝10.4hz,1h),3.33(d,j＝13.4hz,1h),3.19(d,j＝3.8hz,1h),1.62(d,j＝6.0hz,3h),1.11(s,3h),1.02-1.03(d,j＝2.1hz,9h),0.93(s,3h),0.80(s,3h)；
13cnmr(100mhz,dmso,δ):211.12(c-12),178.63(c-28),103.00(c-1’),99.93(c-1”),79.14(c-3),74.24,72.95,72.06,70.50,70.37,68.13,67.89,64.50,62.43,51.12,49.27,46.16,46.08,42.34,41.42,40.75,38.02,37.59,35.88,33.93,31.54,30.36,25.26,23.12,20.18,17.82,15.81,15.39,12.71；
hrms-esi(m/z)[m+na]+:calcd.forc41h66o13na789.4401,found789.4375.
实施例6：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)[β-d-吡喃葡萄糖-(1→4)]-α-l-吡喃阿拉伯糖齐墩果烷-28-酸(化合物20)
步骤6-1：制备化合物14
取化合物4(2.57g，1.99mmol)和无水碳酸钾(827mg，5.99mmol)置于反应瓶中，加入n,n-二甲基甲酰胺(20ml)，边搅拌边滴加溴化苄(0.5ml)，室温下搅拌6小时。反应结束后，加水(100ml)稀释反应体系，得白色乳浊液，用乙酸乙酯(50ml×3)萃取，合并有机层饱和食盐水(50ml×3)洗涤，无水硫酸钠干燥有机层，柱层析硅胶(石油醚：乙酸乙酯＝4:1)得白色固体2.47g，即化合物14，产率90％。
所得固体熔点为164-165℃。所得固体的核磁数据如下：
1hnmr(600mhz,cdcl3,δ):7.28–7.37(m,5h,ar-),5.28(t,j＝3.4hz,1h，h-1”),5.18(t,j＝9.6hz,1h,h-12),4.92(s,1h,h-1’),4.55(d,j＝7.9hz,1h,h-1”’),4.52(d,j＝3.4hz,1h),4.26(dd,j＝12.3,4.7hz,1h),4.15(dd,j＝12.3,2.2hz,1h),4.03(dd,j＝9.1,6.2hz,3h),3.96(dt,j＝16.1,6.2hz,1h),3.81(d,j＝11.5hz,1h),3.76(dd,j＝5.6,3.5hz,1h),3.72(ddd,j＝10.0,4.6,2.4hz,1h),3.57(q,j＝7.2hz,1h),3.42(dd,j＝11.8,4.6hz,1h),2.90(dd,j＝13.6,3.8hz,1h),2.14(s,3h),2.09(s,3h),2.08(s,1h),2.05(s,3h),2.04(s,3h),2.03(s,3h),2.02(s,3h),1.99(s,3h),1.97(s,3h),1.19(d,j＝6.2hz,3h),1.09(s,3h),0.91(s,6h),0.89(s,3h),0.75(s,3h),0.59(s,3h)；
13cnmr(150mhz,cdcl3,δ)177.53(c-28),170.77(ch3co),170.68(ch3co),170.55(ch3co),170.29(ch3co),170.22(ch3co),170.09(ch3co),170.04(ch3co),169.56(ch3co),169.55(ch3co),143.85(c-13),136.55(ar-),128.54(ar-),128.12(ar-),128.05(ar-),122.55(c-12),101.58(c-1”’),101.33(c-1)’,98.22(c-1”),82.06(c-3),74.66,72.96,72.73,71.92,71.10,71.00,69.61,69.01,68.47,67.30,66.07,65.44,61.95,47.96,47.92,46.87,45.99,42.05,41.73,41.53,39.42,38.33,36.67,33.99,33.25,32.53,32.49,30.84,29.84,27.68,25.87,25.18,23.79,23.56,23.16,21.09,21.04,20.96,20.93,20.90,20.85,20.75,20.72,18.17,17.44,17.04,15.94,12.83；
hrms-esi(m/z)[m+na]+:calcdforc72h100o26na1403.6401；found:1403.5948。
步骤6-2：制备化合物16
取化合物14(1.01g，0.732mmol)溶于无水氯仿(20ml)，避光条件下加入75％间氯过氧苯甲酸(337mg，1.25mmol)，室温下避光搅拌24h。反应停止后，真空除去氯仿，得白色固体，加入乙酸乙酯50ml，用10％氢氧化钠溶液(30ml×2)，饱和食盐水(30ml×3)洗涤，无水硫酸钠干燥有机层，回收溶剂得白色固体707mg，即化合物16，直接投入下一步反应。
步骤6-3：制备化合物18
取化合物16(707mg，0.51mmol)溶于无水四氢呋喃(15ml)，加入10％钯碳(50mg)至于氢气环境下搅拌4小时。反应结束后，过滤除去钯碳，柱层析硅胶(石油醚：乙酸乙酯＝5:1)得白色固体600mg，即化合物18，产率90％。
所得固体的熔点为176-177℃。所得固体的核磁数据为：
1hnmr(400mhz,cdcl3,δ):5.23(d,j＝1.0hz,1h,h-1”),5.19–5.22(m,1h,h-12),5.15(d,j＝9.6hz,1h,h-1’),4.89–5.08(m,6h),4.85(d,j＝9.1hz,1h),4.53(d,j＝7.9hz,1h),4.48(d,j＝2.8hz,1h),3.55(d,j＝8.3hz,1h),3.42(s,1h),2.75(d,j＝13.7hz,1h),2.67(d,j＝3.9hz,1h),2.14(s,3h),2.08(s,6h),2.05(s,3h),2.04(s,6h),2.02(s,3h),2.01(s,3h),1.98(s,3h),1.97(s,3h),1.24(s,6h),0.97(s,3h),0.96(s,3h),0.91(s,3h),0.89(d,j＝2.4hz,6h),0.75(s,3h)；
13cnmr(150mhz,cdcl3,δ):211.44(c-12),183.16(cooh),170.76(ch3co),170.67(ch3co),170.54(ch3co),170.30(ch3co),170.20(ch3co),170.07(ch3co),170.04(ch3co),169.54(ch3co),169.52(ch3co),101.59(c-1”’),101.44(c-1’),98.32(c-1”),81.60(c-3),74.81,72.98,72.71,71.90,71.09,70.95,69.57,68.96,68.43,67.31,65.28,61.90,60.53,51.97,50.02,47.91,47.23,42.05,42.01,41.39,38.64,37.79,36.65,36.25,34.56,33.46,33.17,31.95,31.70,31.56,30.74,30.31,29.81,27.63,25.05,23.23,22.74,21.17,21.08,21.01,20.94,20.90,20.87,20.82,20.72,20.69,20.67,18.13,17.45,16.31,15.81,14.32,12.55
hrms-esi(m/z)[m+na]+:calcdforc65h94o27na1329.5881；found:1329.5566。
步骤6-4：制备化合物20
将化合物18(397mg,0.304mmol)溶解于无水甲醇/thf/h2o(2:1:1,20ml)，加入氢氧化钾(205mg,3.65mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(50ml)稀释，饱和食盐水(30ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)得白色固体263mg，即化合物20，产率93％。
所得固体的熔点197–198℃。所得固体的核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):6.28(s,1h,h-1”),5.13(d,j＝7.4hz,1h,h-1’),4.95(d,j＝6.4hz,2h),4.63(d,j＝8.7hz,2h),4.47–4.55(m,2h),4.24–4.44(m,5h),4.11–4.23(m,4h),4.04(s,2h),3.90(s,1h),3.72(d,j＝10.3hz,2h),3.33(d,j＝12.8hz,1h,18βh),3.20(s,1h,13βh),1.66(d,j＝5.2hz,3h,h-6”),1.12(s,3h),1.07(s,3h),1.04(s,6h),0.94(s,3h),0.82(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):211.78(c-12),180.99(cooh),107.14(c-1”’),104.84(c-1’),102.06(c-1”),81.20(c-3),80.86,79.19,78.94,76.63,75.85,75.54,74.49,72.82,72.63,71.57,69.98,65.88,64.14,62.84,52.60,50.61,50.04,48.07,47.69,43.88,42.57,41.94,39.20,38.74,37.17,37.04,35.21,34.10,33.99,33.19,32.47,32.25,32.20,31.37,30.34,28.52,26.55,23.93,23.76,21.55,21.01,19.00,18.46,16.69,16.20,14.11；
hrms-esi(m/z)[m+na]+:calcd.forc47h76o18na951.4930；found:951.4884。
实施例7：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-28-γ-内酯(化合物23)
步骤7-1：制备化合物21
取化合物17(310mg,0.304mmol)、二氯二氰基苯醌(135mg，0.610mmol)溶于无水苯(20ml)，90℃回流48小时。反应结束后，冷却至室温，减压除去溶剂，加入二氯甲烷(30ml)，用饱和碳酸氢钠溶液(20ml×3)洗，取有机层用无水硫酸钠干燥，柱层析硅胶(石油醚：乙酸乙酯＝3:1)得到白色固体145mg，即化合物21，产率48％。
所得固体熔点为208–209℃。所得固体的核磁数据如下：
1hnmr(400mhz,cdcl3,δ):5.24(d,j＝3.2hz,1h,h-1”),5.17–5.22(m,1h,h-1’),4.99–5.08(m,2h,h-11),4.96(dd,j＝9.0,3.4hz,1h),4.39(d,j＝6.6hz,1h),4.05–4.17(m,2h),3.89–4.00(m,2h),3.86(dd,j＝8.9,6.6hz,1h),3.47–3.61(m,2h),2.70(t,j＝14.2hz,1h),2.52(t,j＝8.2hz,1h),2.37(dd,j＝14.5,2.4hz,3h),2.12(s,3h),2.10(s,3h),2.08(s,3h),2.04(s,3h),2.02(s,3h),1.96(s,3h),1.24(s,3h),1.20(d,j＝6.2hz,3h),0.96(s,3h),0.95(s,3h),0.94(s,3h),0.93(s,3h),0.80(s,3h)
13cnmr(100mhz,cdcl3,δ):206.14(c-12),178.54(c-28),170.50(ch3co),170.42(ch3co),170.41(ch3co),170.27(ch3co),170.12(ch3co),169.78(ch3co),103.76(c-1’),98.23(c-1”),91.13(c-13),81.43(c-3),77.36,74.30,72.10,71.12,69.67,68.65,67.98,67.25,65.12,63.08,51.45,47.83,44.10,44.05,43.80,42.60,42.11,38.36,37.49,37.42,37.00,34.24,33.29,32.79,31.68,29.81,29.77,29.47,27.33,27.03,25.93,25.51,23.88,22.80,21.12,21.09,21.05,20.92,20.89,20.77,18.66,18.31,17.45,17.35,16.43,14.24,12.47；
hrms-esi(m/z)[m+cl]+:calcd.forc53h76o19cl1015.4669；found:1015.4671。
步骤7-2：制备化合物23
将化合物21(145mg,0.143mmol)溶解于无水甲醇/thf/h2o(2:1:1,15ml)，加入氢氧化钾(56mg,1.71mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(30ml)稀释，饱和食盐水(20ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得白色固体97mg，即化合物23，产率90％。
所得固体的熔点208–209℃。所得固体的核磁数据如下：
1hnmr(400mhz,cdcl3,δ):6.14(s,1h,h-1”),5.70(s,1h,h-12),4.98(d,j＝5.5hz,1h,h-1’),4.76(s,1h),4.66(dd,j＝9.3,2.7hz,1h),4.16(s,1h),3.76–3.92(m,2h),2.32(t,j＝12.1hz,2h),1.66(d,j＝6.1hz,3h),1.56(s,3h),1.29(s,3h),1.05(s,3h),0.92(s,3h),0.87(s,3h),0.82(s,3h)；
13cnmr(100mhz,cdcl3,δ):206.82(c-12),178.56(c-28),104.94(c-1’),102.12(c-1”),91.57(c-13),81.01(c-3),76.22,75.29,74.54,72.96,72.76,70.08,69.85,66.28,64.17,51.81,47.81,44.72,44.60,44.33,43.96,43.11,39.02,38.04,37.72,37.38,34.63,33.38,33.19,32.02,28.25,26.51,26.47,24.15,21.40,19.03,18.95,18.46,17.69,16.80,13.99；
hrms-esi(m/z)[m-h]-:calcd.forc53h75o191015.4903；found:1015.5097。
实施例8：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)[β-d-吡喃葡萄糖-(1→4)]-α-l-吡喃阿拉伯糖齐墩果烷-28-内酯(化合物24)
步骤8-1：制备化合物22
取化合物18(397mg,0.304mmol)、二氯二氰基苯醌(135mg，0.610mmol)溶于无水苯(20ml)，90℃回流48小时。反应结束后，冷却至室温，减压除去溶剂，加入二氯甲烷(30ml)，用饱和碳酸氢钠溶液(20ml×3)洗，取有机层用无水硫酸钠干燥，柱层析硅胶(石油醚：乙酸乙酯＝3:1)得到白色固体195mg，即化合物22，产率50％。
所得固体熔点为168–169℃。所得固体的核磁数据如下：
1hnmr(600mhz,cdcl3,δ):5.21(s,1h,h-1”),5.19(d,j＝3.1hz,1h,h-1’),5.15(t,j＝9.5hz,1h,h-1”’),4.98–5.06(m,2h,h-11),4.94(dd,j＝24.0,14.4hz,4h),4.50–4.54(m,4h),4.45–4.50(m,1h),4.23(dd,j＝12.3,4.5hz,1h),4.04–4.15(m,2h),3.91–4.03(m,3h),3.81–3.89(m,2h),3.73(dd,j＝5.4,3.9hz,1h),3.69(dd,j＝7.7,2.1hz,1h),3.54(d,j＝8.8hz,1h),3.41(dd,j＝11.7,4.4hz,1h),2.12(s,3h),2.06(s,6h),2.02(s,6h),2.01(s,3h),1.99(s,3h),1.97(s,3h),1.95(s,3h),1.26(s,3h),1.16(d,j＝6.1hz,3h),1.11(s,3h),0.94(s,3h),0.89(s,3h),0.87(s,3h),0.73(s,3h)；
13cnmr(150mhz,cdcl3,δ):206.06(c-12),179.96(c-28),170.71(ch3co),170.61(ch3co),170.45(ch3co),170.23(ch3co),170.16(ch3co),170.03(ch3co),169.98(ch3co),169.51(ch3co),169.49(ch3co),101.49(c-1”’),101.40(c-1’),98.15(c-1”),90.63(c-13),81.77(c-3),76.32,74.58,72.94,72.64,71.84,71.04,70.92,69.55,68.93,68.42,65.30,65.24,61.90,61.85,60.48,51.13,47.85,44.86,44.76,42.34,42.10,42.05,39.45,38.57,36.09,34.19,33.73,33.34,31.63,31.51,30.27,29.75,28.91,28.03,27.53,26.98,25.18,23.97,23.84,21.23,20.98,20.96,20.90,20.86,20.83,20.77,20.67,20.65,18.67,17.55,17.37,16.83,14.27,12.49；
hrms-esi(m/z)[m+cl]+:calcd.forc65h92o27cl1339.5515；found:1339.5978。
步骤8-2：制备化合物24
将化合物22(187mg,0.143mmol)溶解于无水甲醇/thf/h2o(2:1:1,15ml)，加入氢氧化钾(56mg,1.71mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(30ml)稀释，饱和食盐水(20ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝10:1)，得白色固体117mg，即化合物24，产率90％。
所得固体的熔点198–199℃。所得固体的核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):6.26(s,1h,h-1”),5.13(d,j＝7.7hz,1h,h-1’),4.96(d,j＝6.9hz,1h,h-1”’),4.71(s,3h),4.63(dd,j＝9.1,3.3hz,2h),4.50(dd,j＝15.2,8.5hz,3h),4.41–4.33(m,3h),4.30(t,j＝9.3hz,2h),4.25(t,j＝9.1hz,2h),4.18(dd,j＝17.0,10.0hz,6h),4.03(t,j＝16.3hz,3h),3.77(d,j＝10.7hz,1h),3.67(d,j＝12.4hz,1h),2.30(t,j＝12.2hz,2h),1.66(d,j＝6.0hz,3h),1.56(s,3h),1.34(s,3h),1.11(s,3h),0.94(s,3h),0.88(s,3h),0.81(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):206.80(c-12),180.06(c-28),107.06(c-1”’),104.75(c-1’),102.02(c-1”),91.84(c-13),81.40(c-3),80.76,79.12,78.89,76.62,76.09,75.82,75.39,74.46,72.80,72.61,71.57,69.99,65.77,64.21,62.85,52.04,50.02,48.27,45.43,45.31,43.98,43.05,43.02,39.83,39.50,38.97,37.34,37.28,37.18,36.74,34.83,34.50,33.59,33.35,31.97,29.72,28.75,28.63,26.70,26.50,24.15,22.08,19.42,19.09,18.98,18.44,18.03,17.58,16.78,14.09；
hrms-esi(m/z)[m+cl]+:calcd.forc47h74o18cl961.4564；found:961.4791。
实施例9：制备12-肟基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-28-酸(化合物27)
步骤9-1：制备化合物25
取化合物15(300mg，0.270mmol)和盐酸羟胺(100mg，1.36mmol)溶于无水吡啶(15ml)，置于120℃下回流，薄层硅胶色谱检测反应进度。反应结束后，冷却至室温，减压除去吡啶，薄层柱层析(石油醚：乙酸乙酯＝4：1)得到黄色固体213mg，即化合物25，产率74％。
所得固体熔点为161-162℃。所得固体核磁数据如下：
1hnmr(400mhz,cdcl3,δ):7.00-7.50(m,5h,ar-),5.17(s,1h,h-1”),5.13(s,2h),5.11(s,1h),4.99(d,j＝12.0hz,1h,h-1’),4.96(t,j＝9.5hz,2h),4.88(dd,j＝9.7,2.1hz,1h),4.32(d,j＝6.7hz,1h),4.04(t,j＝8.6hz,2h),3.81(dt,j＝15.3,9.2hz,4h),3.46(dd,j＝22.0,8.8hz,2h),2.93(dd,j＝19.0,2.3hz,1h),2.84(d,j＝12.0hz,3h),2.31(s,1h),1.13(d,j＝6.1hz,3h),0.85(s,3h),0.80(s,3h),0.78(s,3h),0.75(s,3h),0.70(s,3h),0.39(s,3h)；
13cnmr(75mhz,cdcl3,δ):178.18(c-28),170.81(ac-),170.74(ac-),170.58(ac-),170.47(ac-),170.06(ac-),160.16(c-12),136.87(ar-c),128.91(ar-c),128.67(ar-c),128.44(ar-c),104.04(c-1’),98.57(c-1”),82.12(c-3),74.67,72.39,71.43,69.97,68.97,68.30,67.55,66.26,65.43,63.32,48.34,48.22,48.04,43.66,42.34,41.36,40.58,38.38,37.01,36.39,35.06,34.00,33.50,33.09,31.87,31.25,30.13,27.54,27.34,25.91,23.55,23.12,23.05,21.42(ch3co),21.38(ch3co),21.25(ch3co),21.10(ch3co),20.23(ch3co),18.30,17.76,16.03,15.83,12.90；
hrms-esi(m/z)[m+na]+:calcdforc60h85no19na1146.5614；found:1146.5215。
步骤9-2：制备化合物26
取化合物25(213mg，0.189mmol)溶于无水四氢呋喃(15ml)，加入10％钯碳(20mg)至于氢气环境下搅拌4小时。反应结束后，过滤除去钯碳，柱层析硅胶(石油醚：乙酸乙酯＝4:1)得黄色固体186mg，即化合物26，产率95％。
所得固体熔点为203-205℃。
1hnmr(400mhz,cdcl3,δ):5.24(d,j＝3.5hz,1h,h-1”),5.18–5.23(m,1h),5.03(t,j＝9.8hz,2h),4.96(dd,j＝9.0,3.4hz,1h,h-1’),4.39(d,j＝6.5hz,1h),4.11(q,j＝7.1hz,4h),3.93(d,j＝10.9hz,2h),3.85(dd,j＝8.8,6.7hz,1h),3.55(dd,j＝16.3,8.8hz,2h),3.03(dd,j＝18.6,5.5hz,1h),2.81(d,j＝13.2hz,1h),2.52(d,j＝2.9hz,1h),2.13(s,3h,ch3co),2.10(s,3h,ch3co),2.10(s,3h,ch3co),2.04(s,3h,ch3co),2.02(s,3h,ch3co),1.96(s,3h,ch3co),1.21(d,j＝6.2hz,3h),0.87-0.91(m,j＝6.9hz,12h),0.84(s,3h),0.79(s,3h)；
13cnmr(100mhz,cdcl3,δ):183.55(c-28),170.53(ch3co),170.51(ch3co),170.43(ch3co),170.28(ch3co),170.17(ch3co),169.76(ch3co),160.61(c-12),103.85(c-1’),98.35(c-1”),81.82(c-3),74.51,72.09,71.15,69.66,68.68,68.03,67.30,65.13,63.12,48.00,47.63,47.30,43.83,42.06,41.03,40.13,37.97,36.79,35.79,34.50,33.76,32.05,30.86,29.82,29.78,23.64,22.82,21.18,21.17,21.11,21.06,20.94,20.90,20.78,20.54,17.47,16.20,15.68,14.32,12.58。
步骤9-3：制备化合物27
取化合物26(186mg，0.179mmol)溶解于无水甲醇/thf/h2o(体积比2:1:1,15ml)，加入氢氧化钾(120mg,1.71mmol)，室温搅拌12h。反应完毕，减压除去有机溶剂，10％hcl调ph至4-5，正丁醇(30ml)稀释，饱和食盐水(20ml×3)洗涤正丁醇层，无水硫酸钠干燥有机层，硅胶柱层析(二氯甲烷:甲醇＝12:1)得淡黄色固体126mg，即化合物27，产率90％。
所得固体熔点为218-219℃。所得固体的核磁数据如下：
1hnmr(400mhz,cd3od,δ):5.12(s,1h,h-1”),4.50(d,j＝4.1hz,1h,h-1’),3.03(d,j＝17.4hz,1h),2.84(d,j＝12.6hz,1h),1.20(d,j＝5.7hz,3h),0.91(s,3h),0.89(s,4h),0.88(s,3h),0.85(s,3h),0.85(s,3h),0.66(s,3h)；
13cnmr(100mhz,pyridine-d5,δ):179.65(c-28),158.25(c-12),104.73(c-1’),101.99(c-1”),81.25(c-3),76.11,75.15,74.44,72.86,72.69,70.00,69.74,66.09,64.18,62.03,49.99,48.69,48.05,43.88,41.85,41.04,39.18,37.27,36.11,31.50,28.41,26.55,23.90,21.45,20.15,19.88,18.97,18.87,18.40,16.43,16.19,14.50,14.06；
hrms-esi(m/z)[m+na]+:calcd.forc41h67no13na804.4510；found:804.4604。
实施例10：制备11-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-n-乙酸-28-甲酰胺(30)
步骤10-1：制备化合物28
化合物5(300g,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体287g，即化合物28，产率95％。
步骤10-2：制备化合物30
化合物28(287mg,0.277mmol)溶解于无水二氯甲烷(10ml)，冰浴冷却下加入甘氨酸乙酯盐酸盐(33mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体184mg，即化合物30，产率约80％。
所得固体熔点为246-247℃。所得固体核磁数据如下：
1hnmr(400mhz,cd3od,δ):5.55(s,1h,h-1”),5.14(s,1h,h-12),4.52(d,j＝2.2hz,1h,h-1’),3.91(d,j＝17.3hz,3h),3.78–3.85(m,3h),3.47(d,j＝11.6hz,3h),3.00(d,j＝10.5hz,1h),2.69(d,j＝13.6hz,1h),2.41(s,1h),1.39(s,3h),1.21(d,j＝6.1hz,3h),1.10(s,3h),0.93(s,3h),0.92(s,3h),0.91(s,3h),0.67(s,3h)；
13cnmr(150mhz,cd3od,δ):202.99(c-11),179.72(coo),173.31(c-28),172.80(c-12),128.22(c-13),104.27,(c-1’)101.80(c-1”),82.00(c-3),76.60,73.87,73.57,72.07,71.97,70.12,69.07,64.71,64.49,63.16,62.02,49.85,47.88,46.95,46.44,45.83,45.02,44.26,42.85(ch2cooh),42.08,40.10,37.96,34.95,33.38,33.24,28.40,26.49,24.08,24.06,23.80,19.79,17.96,17.83,17.22,13.65；
hrms-esi(m/z)[m+na]+:calcdforc43h67no14na844.4459；found:844.4188。
实施例11：制备11-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)[β-d-吡喃葡萄糖-(1→4)]-α-l-吡喃阿拉伯糖齐墩果烷-n-乙酸-28-甲酰胺(化合物31)
化合物6(385g,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体，即化合物29。将上述化合物29溶解于无水二氯甲烷(10ml)，冰浴冷却下加入甘氨酸乙酯盐酸盐(33mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体247mg，即化合物31，产率85％。
所得固体熔点为253-254℃。所得固体核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):8.36(s,1h,nhch2),6.25(s,1h,h-1”),5.99(s,1h,h-1’),5.70(s,1h,h-1”’),5.11(d,j＝7.8hz,1h),4.97(d,j＝6.6hz,1h),4.64(dd,j＝9.2,3.0hz,1h),4.44–4.55(m,2h),3.88(ddd,j＝8.9,4.3,2.2hz,1h),3.75(d,j＝10.5hz,1h),3.29(dd,j＝53.7,12.9hz,2h),2.79(t,j＝7.4hz,1h),2.63(d,j＝11.6hz,1h),1.65(d,j＝6.1hz,3h),1.37(s,3h),1.36(s,3h),1.21(s,3h),1.12(s,3h),0.88(s,3h),0.85(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):200.58(c-11),177.59(cooh),173.99(c-28),170.13(c-12),128.45(c-11),107.03(c-1”),104.76(c-1’),101.99(c-1”’),81.38(c-3),80.64,79.09,78.81,76.57,75.76,75.24,74.41,72.75,72.54,71.52,70.01,65.67,64.20,62.77,61.74,49.99,48.01,46.22,45.82,45.10,44.32,44.25,43.13,42.40,40.21,37.73,34.53,33.28,33.20,31.10,28.24,26.74,23.99,23.85,19.85,18.94,17.59,17.54,14.33；
hrms-esi(m/z)[m-h]-:calcdforc49h76no19982.5012；found:982.5189。
实施例12：制备12-羰基-23羟基-3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖齐墩果烷-n-乙酸-28-甲酰胺(化合物33)
化合物17(290g,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，即得化合物32。化合物32溶解于无水二氯甲烷(10ml)，冰浴冷却下加入甘氨酸乙酯盐酸盐(33mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体209mg，即化合物33，产率约86％。
所得固体熔点为223-224℃。所得固体核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):6.23(s,1h,h-1”),5.05(d,j＝5.7hz,1h,h-12),4.75(s,1h,h-1’),4.60–4.69(m,2h),4.54(d,j＝7.4hz,2h),4.39–4.48(m,1h),4.30(t,j＝9.1hz,1h),4.24(d,j＝9.8hz,1h),4.13(d,j＝10.7hz,1h),4.08(d,j＝5.2hz,1h),3.69(dd,j＝20.5,11.0hz,2h,ch2cooh),3.38(d,j＝19.9hz,2h),1.61(d,j＝5.6hz,3h),1.14(s,3h),1.01(s,9h),0.89(s,3h),0.81(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):211.99(c-12),178.65(cooh),173.93(c-28),104.65(c-1’),101.83(c-1”),81.04(c-3),76.04,74.99,74.30,72.81,72.58,69.92,69.67,66.00,64.10,52.24,50.60,49.95,47.89,47.13,43.77,42.58,42.02,39.17,38.67,37.21,36.95,35.31,34.87,33.94,32.87,32.16,31.18,30.24,28.11,26.36,23.83,23.75,21.01,18.80,18.39,16.84,15.99,13.96；
hrms-esi(m/z)[m-h]-:calcdforc34h70no14824.4796；found:824.4818。
实施例13：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-n-丁酸-28-甲酰胺(化合物35)
化合物3(291mg,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体，即化合物34。将所得化合物34溶解于无水二氯甲烷(10ml)，冰浴冷却下加入氨基丁酸乙酯盐酸盐(94mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体217mg，即化合物35，产率约88％。
所得固体熔点为184-185℃。所得固体核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):7.53(t,j＝5.4hz,1h,conh),5.45(s,1h,h-1”),5.12(d,j＝6.2hz,1h,h-12),4.74(d,j＝2.1hz,1h,h-1’),4.69(td,j＝12.4,6.2hz,1h),4.65(dd,j＝9.3,3.4hz,1h),4.55–4.61(m,1h),4.30(t,j＝9.4hz,1h),4.24–4.28(m,1h),4.18(d,j＝2.5hz,1h),4.15(d,j＝10.9hz,1h),4.09–4.13(m,1h),3.64–3.77(m,3h),3.52(dt,j＝19.4,6.4hz,1h),3.09(dd,j＝13.1,3.7hz,1h),2.63(t,j＝7.2hz,2h),1.64(d,j＝6.2hz,3h),1.20(s,3h),1.07(s,3h),1.00(s,3h),0.98(s,3h),0.93(s,3h),0.89(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):178.03(cooh),176.31(c-28),145.14(c-13),123.22(c-12),104.69(c-1’),101.95(c-1”),81.34(c-3),76.11,75.01,74.42,72.87,72.69,70.02,69.67,65.98,64.27,48.42,47.97,47.07,46.76,43.83,42.46,42.16,40.12,40.06(ch2cooh),39.28,37.17,34.69(nhch2),34.13,33.53,33.01,31.20,30.30,28.27,26.53,26.47,25.98(ch2),24.19,24.10,23.96,18.88,18.45,17.88,16.43,14.32；
hrms-esi(m/z)[m+cl]+:calcdforc45h73no13cl870.4770；found:870.5009。
实施例14：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-n-戊酸-28-甲酰胺(化合物36)
化合物3(291mg,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体，即化合物34。将所得化合物34溶解于无水二氯甲烷(10ml)，冰浴冷却下加入氨基戊酸乙酯盐酸盐(100mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体216mg，即化合物36，产率约86％。
所得固体熔点为185-186℃。所得固体核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):7.38(t,j＝5.5hz,1h，conh),6.27(s,1h,h-1”),5.44(s,1h,h-12),4.75(s,1h,h-1’),4.71(dt,j＝15.4,6.2hz,1h),4.66(dd,j＝9.3,3.2hz,1h),4.57–4.61(m,1h),4.24–4.34(m,2h),4.12(dd,j＝7.8,3.3hz,1h),3.77(d,j＝10.7hz,1h),3.71(d,j＝11.1hz,1h),3.48–3.56(m,1h),3.37(dt,j＝19.1,9.4hz,1h),3.07(dd,j＝13.0,3.5hz,1h),2.35(t,j＝7.2hz,2h),2.23(dd,j＝13.0,3.2hz,1h),1.65(d,j＝6.1hz,3h),1.21(s,3h),1.10(s,3h),1.02(s,3h),0.99(s,3h),0.94(s,3h),0.90(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):177.89(cooh),174.10(c-28),145.22(c-13),123.21(c-12),104.75(c-1’),102.00(c-1”),81.36(c-3),76.12,75.11,74.47,72.91,72.73,69.98,69.73,66.08,64.30,51.65,48.45,48.02,47.11,46.80,43.87,42.52,42.22,40.15(ch2),39.75,39.34,37.22,34.73,34.17,34.09(ch2),33.54,33.06,31.23,29.92(ch2),28.28,26.57,26.47,24.20,24.09(ch2),24.02,23.17,18.91,18.48,17.88,16.46,14.37；
hrms-esi(m/z)[m+na]+:calcdforc46h75no13na872.5136；found:872.4962。
实施例15：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-n-己酸-28-甲酰胺(化合物37)
化合物3(291mg,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体，即化合物34。将所得化合物34溶解于无水二氯甲烷(10ml)，冰浴冷却下加入氨基己酸乙酯盐酸盐(107mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体219mg，即化合物37，产率约86％。
所得固体熔点为188-189℃。所得固体核磁数据如下：
1hnmr(400mhz,pyridine-d5,δ):7.32(t,j＝4.0hz,1h，conh),6.30(s,1h,h-1″),5.46(s,1h,h-12),5.13(d,j＝6.4hz,1h,h-1′),4.70-4.74(m,1h),4.67(dd,j＝9.4,3.3hz,1h),4.61(t,j＝7.1hz,1h),4.24-4.38(m,2h),4.19(d,j＝3.9hz,2h),4.12(dd,j＝7.9,3.4hz,1h),3.74(dd,j＝19.4,10.7hz,2h),3.49-3.59(m,1h),3.42-3.31(m,1h),3.09(dd,j＝13.7,2.9hz,1h),2.51(t,j＝7.3hz,2h),1.66(d,j＝6.0hz,3h),1.21(s,3h),1.10(s,3h),1.02(d,j＝1.5hz,6h),0.94(s,3h),0.90(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):177.80(cooh),176.19(c-28),145.31(c-13),123.19(c-12),104.76(c-1′),102.02(c-1″),81.37(c-3),76.12,75.14,74.49,72.91,72.75,70.05,69.74,66.10,64.30,50.02,48.47,48.04,47.14,46.77,43.88,42.54,42.26,40.17,40.13(ch2),39.34,37.23,35.15(ch2),34.76,34.14,33.55,33.08,31.23,30.24(ch2),28.29,27.56(ch2),26.58,26.47,25.67(ch2),24.25,24.10,18.92,18.49,17.92,16.48,14.38；
hrms-esi(m/z)[m+k]+:calcdforc47h77kno13902.5032；found:902.4871。
实施例16：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-n-乙酰甘氨酸-28-甲酰胺(化合物38)
化合物3(291mg,0.295mmol)溶于无水二氯甲烷(15ml)中，冰浴冷却下加入草酰氯(0.1ml,1.17mmol)，室温下搅拌4h。反应结束，减压除去溶剂及过量的草酰氯，得黄色固体，即化合物34。将所得化合物34溶解于无水二氯甲烷(10ml)，冰浴冷却下加入氨基酸乙酯盐酸盐(109mg，0.554mmol)、三乙胺(84.4mg,0.831mmol)，室温反应12h。反应结束，加入50ml二氯甲烷，用饱和食盐水洗(50ml×3)，无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。将白色固体溶解于混合溶剂(ch3oh/thf/h2o＝2:1:1(v/v/v)，20ml)，加入氢氧化钾(187mg，3.324mmol)，室温搅拌12h。反应完毕，减压除去大部分有机溶剂溶剂，用10％hcl调节ph为2，用正丁醇萃取(20ml×3)。无水硫酸钠干燥，滤过，减压浓缩除去溶剂得白色固体。柱层析色谱(二氯甲烷：甲醇＝10:1)得到白色固体211mg，即化合物38，产率约83％。
所得固体熔点为290-291℃。所得固体核磁数据如下：
1hnmr(600mhz,pyridine-d5,δ):6.24(s,1h,h-1”),5.42(s,1h,h-12),5.12(d,j＝6.2hz,1h,h-1’),4.74(d,j＝2.1hz,1h),4.69(td,j＝12.4,6.2hz,1h),4.64(dd,j＝9.3,3.4hz,1h),4.53–4.61(m,1h),4.23–4.32(m,3h),4.17(dd,j＝14.6,6.6hz,2h),4.10(tdd,j＝10.9,7.0,3.8hz,2h,nhch2co),3.73(dd,j＝30.6,10.4hz,2h,ch2cooh),3.54–3.66(m,1h),3.45(dt,j＝12.7,6.6hz,1h),3.08(dd,j＝13.0,4.1hz,1h),2.50(t,j＝7.4hz,1h),2.25–2.18(m,1h),1.64(s,3h),1.20(s,3h),1.09(s,3h),1.01(s,3h),0.99(s,3h),0.93(s,3h),0.90(s,3h)；
13cnmr(150mhz,pyridine-d5,δ):178.07(cooh),174.03(conh),173.68(conhconh),145.13(c-13),123.17(c-12),104.69(c-1’),101.95(c-1”),81.33(c-3),76.10,75.01,74.41,72.86,72.68,70.02,69.66,65.99,64.55,64.27,51.70,48.41,47.98,47.05,46.76,43.84,42.48,42.12,40.12,39.71,39.30,37.18,34.69,34.17,33.51,33.04,31.24,28.25,26.45,24.17,24.08,23.95,19.68,18.87,17.91,16.45,14.31；
hrms-esi(m/z)[m+cl]+:calcdforc45h72no14cl899.4672；found:899.4972。
实施例17：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-2-溴-28-甲酸乙酯(化合物42)
取化合物1(400mg，0.53mmol)和碳酸钾(220mg，1.60mmol)置于反应瓶中，加入n，n-二甲基甲酰胺(15ml)，滴加入二溴乙烷(120mg，0.64mmol)室温下搅拌6小时。反应结束后，加蒸馏水(100ml)稀释，正丁醇(30ml×3)萃取，合并有机层，饱和食盐水(30ml×3)洗涤有机层，无水硫酸钠干燥，过滤，减压除去正丁醇，得白色蜡状固体，即化合物39。将所得化合物39置于反应瓶中，另小心取硝酸银(308mg，1.81mmol)，在避光条件下加入反应瓶中，加入乙腈(25ml)，室温下搅拌十分钟，然后升温至60℃回流4小时。反应停止后，抽滤除去固体，减压除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝15:1)，得到白色蜡状固体364mg，即化合物42。两步产率86％。
所得固体熔点为153-154℃。所得固体核磁数据如下：
1hnmr(400mhz,pyridine-d5,δ):6.28(s,1h,h-1”),5.37(t,j＝3.2hz,1h,h-12),5.11(d,j＝6.3hz,1h,h-1’),4.89(dd,j＝6.2,2.6hz,2h,ch2ono2),4.75(d,j＝4.3hz,1h),4.68–4.74(m,1h),4.66(dd,j＝9.3,3.4hz,1h),4.56(ddd,j＝9.2,6.3,5.2hz,4h),4.22–4.38(m,3h),4.04–4.21(m,4h),3.73(dd,j＝24.2,11.3hz,2h,cooch2),3.05(dd,j＝15.1,2.0hz,1h),2.21(dd,j＝12.6,3.0hz,1h),1.64(d,j＝6.2hz,3h),1.15(s,3h),1.08(s,3h),0.97(s,3h),0.91(s,3h),0.88(s,3h),0.86(s,3h)；
13cnmr(100mhz,pyridine-d5,δ):177.61(c-28),143.98(c-13),123.32(c-12),104.75(c-1’),101.98(c-1”),81.23(c-3),76.08,75.09,74.43(ch2ono2),72.83,72.66,72.05,69.94,69.72,66.10,64.19,61.04(cooch2),48.28,47.92,47.30,46.13,43.78,42.20,41.98,39.95,39.23,37.10,34.09,33.61,33.32,32.96,31.02,28.25,26.50,26.30,24.06,23.87,23.52,18.86,18.38,17.49,16.35,14.30；
hrms-esi(m/z)[m+h]+:calcdforc43h70no15840.4745；found:840.4564。
实施例18：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-4-溴-28-甲酸丁酯(化合物43)
取化合物1(400mg，0.53mmol)和碳酸钾(220mg，1.60mmol)置于反应瓶中，加入n，n-二甲基甲酰胺(15ml)，滴加入二溴丁烷(138mg，0.64mmol)室温下搅拌6小时。反应结束后，加蒸馏水(100ml)稀释，正丁醇(30ml×3)萃取，合并有机层，饱和食盐水(30ml×3)洗涤有机层，无水硫酸钠干燥，过滤，减压除去正丁醇，得白色蜡状固体，即化合物40。将所得化合物40置于反应瓶中，另小心取硝酸银(308mg，1.81mmol)，在避光条件下加入反应瓶中，加入乙腈(25ml)，室温下搅拌十分钟，然后升温至60℃回流4小时。反应停止后，抽滤除去固体，减压除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝15:1)，得到白色蜡状固体372mg，即化合物43。两步产率81％。
所得固体熔点为141-142℃。所得固体核磁数据如下：
1hnmr(400mhz,pyridine-d5,δ):6.24(s,1h,h-1”),5.35(s,1h,h-12),5.07(d,j＝6.3hz,1h,h-1’),4.72(d,j＝1.9hz,1h),4.67(dd,j＝9.4,6.2hz,1h),4.62(dd,j＝9.3,3.3hz,1h),4.54(dt,j＝10.3,7.1hz,2h,ch2ono2),4.26(dd,j＝20.9,11.3hz,3h),4.17(t,j＝5.9hz,2h,cooch2),4.07–4.14(m,2h),3.70(dd,j＝23.6,10.5hz,2h),3.04(dd,j＝12.9,3.0hz,1h),2.17(dd,j＝12.8,3.2hz,1h),1.60(d,j＝6.2hz,3h),1.15(s,3h),1.05(s,3h),0.94(s,3h),0.91(s,3h),0.87(s,3h),0.85(s,3h)；
13cnmr(100mhz,pyridine-d5,δ):177.51(c-28),144.25(c-13),123.02(c-12),104.55(c-1’),101.71(c-1”),81.00(c-3),75.82,74.88,74.21,73.71(ch2ono2),72.67,72.45,69.71,69.53,65.91,63.98,63.78(cooch2),49.83,48.09,47.72,47.02,46.07,43.59,42.09,41.88,39.81,39.06,36.92,34.01,33.20,32.98,32.86,30.88,30.04(ch2),28.10,26.29,26.14,25.40(ch2),23.97,23.74,23.42,18.68,18.19,17.50,16.16,14.15；
hrms-esi(m/z)[m+h]+:calcdforc45h74no15868.5058；found:868.4859。
实施例19：3-o-α-l-吡喃鼠李糖-(1→2)-α-l-吡喃阿拉伯糖常春藤皂苷-6-溴-28-甲酸己酯(化合物44)
取化合物1(400mg，0.53mmol)和碳酸钾(220mg，1.60mmol)置于反应瓶中，加入n，n-二甲基甲酰胺(15ml)，滴加入二溴己烷(156mg，0.64mmol)室温下搅拌6小时。反应结束后，加蒸馏水(100ml)稀释，正丁醇(30ml×3)萃取，合并有机层，饱和食盐水(30ml×3)洗涤有机层，无水硫酸钠干燥，过滤，减压除去正丁醇，得白色蜡状固体，即化合物41。将所得化合物41置于反应瓶中，另小心取硝酸银(308mg，1.81mmol)，在避光条件下加入反应瓶中，加入乙腈(25ml)，室温下搅拌十分钟，然后升温至60℃回流4小时。反应停止后，抽滤除去固体，减压除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝15:1)，得到白色蜡状固体370mg，即化合物44。两步产率78％。
所得固体熔点为126-127℃。所得固体核磁数据如下：
1hnmr(400mhz,pyridine-d5,δ):6.27(s,1h,h-1”),5.39(s,1h,h-12),5.10(d,j＝6.3hz,1h,h-1’),4.74(dd,j＝3.2,1.4hz,1h),4.70(dd,j＝9.4,6.2hz,1h),4.65(dd,j＝9.3,3.4hz,1h),4.54–4.61(m,1h),4.43(t,j＝6.6hz,2h,ch2ono2),4.28(dt,j＝12.0,6.7hz,3h),4.15–4.21(m,4h,cooch2),4.12(dd,j＝7.8,3.3hz,1h),3.73(dd,j＝26.2,10.4hz,2h),3.10(dd,j＝14.1,1.3hz,1h),2.21(dd,j＝13.0,3.5hz,1h),1.63(d,j＝6.2hz,3h),1.18(s,3h),1.08(s,3h),0.98(s,3h),0.95(s,3h),0.90(d,j＝1.8hz,6h)；
13cnmr(100mhz,pyridine-d5,δ):177.74(c-28),144.45(c-13),123.14(c-12),81.20(c-3),76.02,75.06,74.40,74.18(ch2ono2),72.83,72.63,69.91,69.69,66.07,64.47,64.18(cooch2),48.28,47.92,47.16,46.26,43.76,42.26,42.04,40.00,39.12,37.10,34.21,33.36,33.21,33.04,31.07,28.99(ch2),28.30,27.03(ch2),26.49(ch2),26.31,26.14,25.72(ch2),24.06,23.90,23.61,18.84,18.35,17.70,16.33,14.29；
hrms-esi(m/z)[m+h]+:calcdforc47h78no15896.5371；found:896.5157。
实施例20：细胞毒实验
实验目的：
通过体外培养人肺癌细胞a549，人肝癌细胞smmc-7721，人胃癌细胞bgc-823，采用mtt法检测细胞增殖活性，筛选受试化合物的体外抗肿瘤活性。
实验材料：
1.受试细胞株：人肺癌细胞a549、人肝癌细胞smmc-7721，人胃癌细胞bgc-823胞株，购自中国科学院上海生命科学研究院细胞资源中心。
2.噻唑蓝mtt，购自上海国药集团。
3.受试药物：本发明合成的皂苷衍生物。
4.阳性对照物：α-常春藤皂苷(编号为psa)，白头翁皂苷d(编号为psd)，顺铂(cis-ddp)。
实验方法：
1.受试药物的配制各受试药物浓度设置：100μm、50μm、25μm、12.5μm、6.25μm；均用少量dmso溶解后(0.5％以内)，用相应培养基配制后，0.22μm过滤备用。
2.细胞增殖抑制实验取对数生长期细胞，调整密度为8×104加入不同浓度含药培养基100μl，对照组每孔加培养基100μl，对照组与药物组均设3个复孔，另设空白对照组，不加细胞只加培养基的作为对照组调零。将96孔板置5％co2培养箱(37℃)培养48h，加入5mg/mlmtt20μl，继续培养4h后，弃上清，加入dmso150μl，振荡溶解10min，酶标仪于490nm处测定od值。
3.观察指标
按公式计算抑制率，计算三次平行试验的ic50平均值，结果参见表1。
抑制率(％)＝[(1-用药组平均od值/对照组平均od值)]×100％。
表1：psa/psd衍生物的体外抗肿瘤活性及溶血毒性数据
实施例21：溶血实验
21.1血细胞悬液制备
取健康家兔1只，自耳缘静脉取血约10ml，置于预先放有玻璃珠的三角瓶中振摇10min，搅拌去纤维蛋白，使之成为脱纤血液。然后将血移入刻度离心管内，加入0.9％氯化钠溶液约10倍量，混匀后离心15min(1000-1500r/min)，去除上清液，再加0.9％氯化钠溶液混匀离心，反复洗3～4次，至上清液无色透明，将所得红细胞按其容积用生理盐水稀释成2％的混悬液。
21.2试验方法
取洁净试管7只进行编号，1-6号管为受试药物管，终浓度依次为100μg/m、50μg/m、25μg/m、12.5μg/m、6.25μg/m、3.125μg/ml，7号管阴性对照管，8号管为阳性对照管。依次加入2％红细胞悬液、0.9％氯化钠溶液或蒸馏水、受试药物，混匀后，立即置于37±0.5℃的水浴中进行温育，开始每隔15分钟观察1次，1小时后，每隔1小时观察1次，一共观察3小时。根据红细胞释放出来的血红素在可见波长段具有最大吸收的原理，采用分光光度法测定各受试药物的溶血程度。将温育了3h后的各管受试药物溶液离心，取上清，在酶标仪545nm处，以蒸馏水为空白读取各管的od值。
21.3结果判断：用下式计算各试验管的溶血率(％)。
溶血率(％)＝(odt-odnc)/(odpc-odnc)
其中：odt是受试药物管吸光度；odnc是阴性对照管吸光度；odpc是阳性对照管吸光度。
接公式计算抑制率，并采用软件计算hd50，结果参见表1。
通过以上实施例20和21可以看出，本发明的皂苷衍生物与α-常春藤皂苷相比，该皂苷衍生物具有较强的抗肿瘤活性，但其溶血毒性大大降低，适用于治疗或辅助治疗肿瘤。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。