CN106831924B - 一种膜荚黄芪皂苷ⅱ的合成方法 - Google Patents
一种膜荚黄芪皂苷ⅱ的合成方法 Download PDFInfo
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- CN106831924B CN106831924B CN201710177839.6A CN201710177839A CN106831924B CN 106831924 B CN106831924 B CN 106831924B CN 201710177839 A CN201710177839 A CN 201710177839A CN 106831924 B CN106831924 B CN 106831924B
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- saponin
- cycloastragenol
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- 239000001397 quillaja saponaria molina bark Substances 0.000 title claims abstract description 19
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- 150000007949 saponins Chemical class 0.000 title claims abstract description 19
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- 235000006533 astragalus Nutrition 0.000 title claims abstract description 17
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
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- 230000004224 protection Effects 0.000 claims abstract description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 32
- WENNXORDXYGDTP-UOUCMYEWSA-N cycloastragenol Chemical compound O1[C@H](C(C)(O)C)CC[C@]1(C)[C@@H]1[C@@]2(C)CC[C@]34C[C@]4(CC[C@H](O)C4(C)C)[C@H]4[C@@H](O)C[C@H]3[C@]2(C)C[C@@H]1O WENNXORDXYGDTP-UOUCMYEWSA-N 0.000 claims abstract description 25
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- 238000000034 method Methods 0.000 claims abstract description 11
- 125000006239 protecting group Chemical group 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 35
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical group [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
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- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
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- LVBLYMQWWGLBRE-UHFFFAOYSA-N Astragaloside-II Chemical compound CC(=O)OC1C(C(COC1OC2CCC34CC35CCC6(C(C(CC6(C5CC(C4C2)OC7C(C(C(C(O7)CO)O)O)O)C)O)C8(CCC(O8)C(C)(C)O)C)C)O)O LVBLYMQWWGLBRE-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
Abstract
本发明公开了一种膜荚黄芪皂苷Ⅱ的合成方法,包括以下步骤:(1)通过TBS选择性保护环黄芪醇3位羟基;(2)通过Ac保护环黄芪醇6,16,20位羟基,(3)选择性脱除3位羟基;(4)构建3位糖苷键;(5)脱除分子中所有的保护基得到膜荚黄芪皂苷Ⅱ。本发明方法有效的实现了环黄芪醇中3位羟基的区分,高效高立体选择性的构建了的3位糖苷键,有效的合成膜荚黄芪皂苷Ⅱ,填补了现有技术的空白,将大大推进黄芪皂苷类化合物的活性机理研究及其药物开发的进程。
Description
技术领域
本发明属于化学合成领域,更具体的涉及一种膜荚黄芪皂苷Ⅱ的合成方法。
背景技术
黄芪,是中医中重要的补气药物,具有补气升阳、益卫固表、脱毒排脓、敛拖生肌等功效。现代研究表明,黄芪具有免疫增强作用、抗衰老作用、抗肿瘤作用、保护心脑血管、保护肝肾等作用,是补气益中药物中应用最为广泛的中药品种,在许多中药复方中作为主药,是目前用量最大的中药材之一。
近年来随着现代分离和鉴定技术的发展,从黄芪中分离出了大量三萜皂苷、黄酮类化合物以及多糖类成分。后期的生物生化实验表明黄芪的药用功效主要通过黄芪皂苷表现出来。近期研究表明,黄芪皂苷在免疫调节,降糖,改善胰岛素抵抗活性,抗肿瘤,对心血管***调节以及抗病毒,抗氧化活性等方面都表现出了极为可喜的药用前景。
尽管黄芪皂苷广泛的应用前景促使人们对其研究不断深入,但目前用于活性测试的黄芪皂苷多为从黄芪中分离提取所得,由于黄芪中所含皂苷种类繁多,且结构类似,这给分离提纯带来很大困难。还有一些黄芪皂苷为次生皂苷,在黄芪中的含量很低,要得到足够量以供活性测试之用更是不易,这已成为制约黄芪皂苷活性研究深入的瓶颈,到目前为止几乎没有关于黄芪皂苷的化学合成研究报道。
膜荚黄芪皂苷Ⅱ(Astramembrannin II),结构式见式I,在总黄芪皂苷中的质量百分含量为0.42%。其甙元部分为环黄芪醇(结构式见化合物1),由于环黄芪醇(化合物1)的3位,6位,16位及25位含有4个惰性OH,4个惰性OH相互之间的反应活性难以区分,选择性的糖苷化其中部分羟基非常困难。
环黄芪醇的羟基保护反应进行困难且产物复杂多变,有文献报道,在过量乙酰化试剂作用下,60℃,长达50天的反应时间下,仅能得到56%收率的全乙酰化的环黄芪醇。缩短反应时间或降低反应温度导致反应产物十分复杂,为4个羟基中随机的1或2个羟基被保护的环黄芪醇。
文献中常用的对大位阻、惰性的羟基保护的方法在环黄芪醇保护中也不起作用,例如路易斯酸催化的乙酰化反应得不到选择性保护的环黄芪醇。
因此黄芪皂苷合成国内外至今未见成功的报道,膜荚黄芪皂苷Ⅱ的合成也未见报道。人工合成膜荚黄芪皂苷Ⅱ,以获得足够量的该化合物,有助于进一步推进对其生物活性,药理活性的研究,有很高的学术及社会经济价值。
参考文献:
a)Mamedova,R.P.;Agzamova,M.A.;Isaev,M.I.Chem.Nat.Compd.2001,37,533-536.b)Isaev,I.M.;Iskenderov,D.A.;Isaev,M.I.Chem.Nat.Compd.2009,45,381-384.c)Isaev,I.M.;Iskenderov,D.A.;Isaev,M.I.Chem.Nat.Compd.2010,46,407-411.d)Procopiou,P.A.;Baugh,S.P.D.;Flack,S.S.;Inglis,G.G.J.Org.Chem.1998,63,2342-2347.d)Kitagawa,I.;Wang,H.-K.;Saito,M.;Yoshikawa,M.Chem.Pharm.Bull.1983,31,709-715.e)Hirotani,M.;Zhou,Y.;Rui,H.;Furuya,T.Phytochemistry 1994,37,1403-1407.
发明内容
本发明要解决的技术问题是:开发一种合成膜荚黄芪皂苷Ⅱ的方法,以获得足够量的该化合物,进一步推进对其生物活性,药理活性的研究。
为解决上述技术问题,本发明采取的技术方案是:
一种膜荚黄芪皂苷Ⅱ的合成方法,包括以下步骤:
(1)3位羟基选择性保护:将环黄芪醇溶于第一溶剂中,在碱性条件下,与硅基化试剂作用反应,得到3位羟基选择性保护的化合物2;
(2)6,16,25位羟基选择性保护:0℃以下,将化合物2和PPy溶于第二溶剂中,再加入酸酐和DIPEA,将反应温度缓慢升至室温后再加热到100~120℃,继续反应直到TLC跟踪显示反应完全,得到6,16,25位羟基保护的化合物3;
(3)选择性脱除3位羟基:将化合物3溶于第三溶剂中,酸性条件下脱除3位保护基,得到化合物4;
(4)构建3位糖苷键:将化合物4和木糖炔酯给体5溶于第四溶剂中,并加入干燥剂,在室温下搅拌后,加入催化剂,继续在室温下反应,直到TLC跟踪显示化合物4反应完全,得到化合物6;
(5)最终脱保护:在碱性条件下,第五溶剂中,将化合物6的所有保护基脱除,即得膜荚黄芪皂苷Ⅱ,
其中,所述R1选自烷硅基;所述R2选自取代或非取代的C2-C6烷酰基;所述R3选自取代或非取代的C1-C6芳酰基;X选自取代或非取代的炔苯甲酰氧基。
优选的,R1选自大位阻的烷硅基,更优选的R1选自TBS或TBDPS。
优选的,所述R2选自乙酰基、丙酰基、丁酰基、异丙酰基;优选的,R3选自苯甲酰基、对甲基苯甲酰基或邻甲基苯甲酰基;优选的,X任选自所述以下基团之一:
最优选的,X为
步骤(1)中,所述第一溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;优选的,所述第一溶剂选自干燥的二氯甲烷、DMF、THF或甲苯中的一种或多种。所述化合物1在所述第一溶剂中的浓度为0.1~1.5mol/L,优选为1.36~1.5mol/L。
步骤(1)中,所述硅基化试剂选自TBSCl,所述碱选自三乙胺、咪唑或二异丙基乙基胺中的一种或多种,化合物1、所述硅基化试剂和所述碱的摩尔比为1:1.5:2~1:4:6,优选为1:2:4~1:4:6。环黄芪醇含有4个羟基,常规情况下,多羟基反应底物选择性保护其中一个羟基时,保护基试剂和底物的摩尔比不可过量,否则容易生成羟基过度保护的产物,但在本发明中,保护基试剂和底物的的摩尔比高达4个当量时,仍无明显羟基过度保护的产物生成。
步骤(2)中,所述第二溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,优选的,所述第二溶剂为甲苯或1,2-二氯乙烷;所述化合物2在所述第二溶剂中的浓度为0.1~5mol/L,优选为0.11~0.5mol/L。
步骤(2)中,所述酸酐选自取代或非取代的C2-C6脂肪酸的酸酐,优选为乙酸酐、丙酸酐、丁酸酐、异丙酸酐;最优选为乙酸酐;所述化合物2、PPy、酸酐和DIPEA的摩尔比为1:1.5:8:12~1:2:15:20,优选为1:2:10:15~1:2:15:20。
步骤(3)中,所述第三溶剂为甲醇,化合物3在所述第三溶剂中的浓度为0.014~0.5mol/L;所述酸为樟脑磺酸,所述化合物3和樟脑磺酸的摩尔比为1:3~1:4。
步骤(4)中,所述催化剂选自一价金的络合物;优选为PPh3AuNTf2或PPh3AuOTf;所述干燥剂选自分子筛,优选的为分子筛或酸洗的分子筛,更优选的为4A分子筛,所述分子筛相对化合物4的加入量为100~300g/mol。所述干燥剂选自分子筛;化合物4、木糖炔酯给体5和催化剂的摩尔比为1:1:0.1~1:5:0.8,优选为1:1:0.1~1:2:0.5。
加入分子筛后搅拌时间可为0.5~2小时,以充分干燥溶剂为准。
步骤(4)中,所述第四溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,优选的,所述第四溶剂为二氯甲烷。所述化合物4在第四溶剂中的浓度为0.001~1mol/L,优选为0.01~0.08mol/L。。
步骤(5)中,所述碱选自甲醇钠、氢氧化钠、碳酸钾、氢氧化钾;所述化合物6和所述碱的摩尔比为1:7~20,优选为1:7~10。
步骤(5)中,所述第五溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,优选为甲醇;所述化合物6在第五溶剂中的浓度为0.001~1mol/L,优选为0.01~0.016mol/L。。
优选的,步骤(1)~(5)中,在惰性气体气氛中反应,所述惰性气体选自氮气、氩气或氦气。
优选的,步骤(1)~(5)中,使用的溶剂,使用前先干燥除水。
本发明中,R的上标表示基团的序号,下标表示有几个基团,例如R1 2表示两个R1基团。
有益效果:本发明高效高立体选择性高收率的制备了膜荚黄芪皂苷Ⅱ,填补现有技术的空白,将大大推进黄芪皂苷类化合物的活性机理研究及其药物开发的进程。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
本发明中PPy表示4-吡咯烷基吡啶(英文名:4-(1-pyrrolidino)-pyridine)),DIPEA表示N,N-二异丙基乙胺;以下每步反应得到的产物纯度较高,在400兆核磁共振氢谱中见不到杂质峰。
Bz保护的糖5按照本领域常规方法合成,参考文献Chem.Sci.2013,4,3899-3905.
在氮气保护,将异头位羟基裸露的全Bz木糖(0.17mmol)溶于干燥的二氯甲烷(4mL)中,再向体系中加入邻炔基苯甲酸(0.2mmol),DMAP(0.23mmol),EDCI(0.23mmol),DIPEA(0.45mmol),室温下搅拌过夜直到TLC跟踪显示原料反应完全,将反应体系用二氯甲烷萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物5。(612mg,89%):[α]D 25=0.02(c 1.0,CHCl3);1H NMR(400MHz,CDCl3)δ8.04-7.98(m,6H),7.90(dd,J=1.2,8.0Hz,1H),7.58-7.51(m,3H),7.49-7.42(m,2H),7.38-7.30(m,6H),7.21(td,J=1.6,7.6Hz,1H),6.42(d,J=7.6Hz,1H),5.81(t,J=5.2Hz,1H),5.58(dd,J=4.0,5.2Hz,1H),5.36-5.32(m,1H),4.63(dd,J=3.6,12.8Hz,1H),4.06(dd,J=4.8,12.4Hz,1H),1.54-1.47(m,1H),0.90-0.84(m,4H);13C NMR(100MHz,CDCl3)δ164.9,164.4,164.3,163.3,133.7,132.8,129.9,129.7,129.4,129.3,128.5,128.3,127.8(2C),126.3,124.7,99.7,91.4,73.6,67.8,67.6,67.2,60.9,8.2,-0.0;HRMS(ESI-TOF)m/z:[M+H]+calcd for C38H31O9 631.1968;found 631.1966.
实施例1:
(1)3位羟基保护的环黄芪醇衍生物3的合成
在氮气保护下,将环黄芪醇(400mg,0.82mmol)溶于干燥的DMF(0.6mL)再向体系中加入TBSCl(489mg,3.27mmol),咪唑(333mg,4.90mmol),在室温搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物2(376.5mg,76.8%):[α]D 25=30.5(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ4.67(dd,J=7.6,14.4Hz,1H),3.72(dd,J=6.0,8.0Hz,1H),3.51(td,J=3.6,9.6Hz,1H),3.25(dd,J=4.8,10.0Hz,1H),2.59(dd,J=10.4,21.6Hz,1H),2.31(d,J=8.0Hz,1H),2.00-1.92(m,4H),1.76(dd,J=4.0,12.0Hz,1H),1.25(s,3H),1.21(s,3H),1.17(s,3H),1.13(s,3H),1.11(s,3H),1.09(s,3H),0.91(s,3H),0.89(s,3H),0.85(s,9H),0.47(d,J=4.0Hz,1H),0.31(d,J=4.4Hz,1H),0.00(s,3H),-0.005(s,3H);13C NMR(100MHz,CDCl3)δ87.1,81.4,78.8,73.4,71.8,68.9,57.5,53.7,46.9,46.5,46.0,45.0,42.1,37.7,34.4,33.0,32.1,31.4,30.8,29.4,28.6,27.9,27.7,26.4,25.9(2C),25.8,21.4,20.5,20.0,18.1,15.8;HRMS(ESI)calcd forC36H65O5Si[M+H]+605.4596,found 605.4599.
(2)全羟基保护的环黄芪醇衍生物3的合成
在氮气保护,0摄氏度条件下,化合物2(133mg,0.22mmol),PPy(58mg,0.44mmol)溶于干燥的甲苯(2ml)中,再向体系中加入乙酸酐(0.18ml,2.2mmol),DIPEA(0.479ml,3.3mmol),体系缓慢升至室温然后在加热到105摄氏度,搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物3(139.7mg,99%):[α]D 25=78.3(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ5.31(m,1H),4.70(td,J=4.8,8.8Hz,1H),3.96(t,J=7.2Hz,1H),3.24(m,1H),2.40(d,J=8.0Hz,1H),2.14(m,1H),2.13(dd,J=8.0,13.6Hz,1H),1.98(s,3H),1.95(s,3H),1.93(s,3H),1.40(s,3H),1.38(s,3H),1.29(s,3H),0.92(s,3H),0.85(s,15H),0.84(s,3H),0.54(d,J=4.8Hz,1H),0.27(d,J=4.8Hz,1H),0.00(s,6H);13C NMR(100MHz,CDCl3)δ170.4(2C),170.2,85.6,83.1,81.3,78.4,75.8,70.6,57.5,49.6,46.5,46.3,45.4,44.6,41.8,37.3,32.8,32.3,31.6,30.6,28.8,28.4,27.0(2C),26.2,26.0,25.9,22.8,22.5,21.8,21.6,21.5,20.5,20.2,19.9,18.1,15.5;HRMS(ESI)calcd for C42H71O8Si[M+H]+731.4913,found 731.4912.
(3):3位羟基裸露的环黄芪醇衍生物4的合成
在氮气保护下,将化合物3(20mg,0.03mmol)溶于干燥的甲醇(2mL)中,在室温下加入樟脑磺酸(26mg,0.11mmol),搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物4(15mg,88.9%):[α]D 25=162.2(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ5.35-5.30(m,1H),4.76(td,J=4.4,9.2Hz,1H),4.02(t,J=7.6Hz,1H),3.32(dd,J=3.6,10.8Hz,1H),2.43(d,J=8.0Hz,1H),2.18-2.12(m,2H),2.01(s,3H),2.00(s,3H),1.97(s,3H),1.43(s,3H),1.41(s,3H),1.324(s,3H),1.319(s,3H),0.99(s,3H),0.96(s,3H),0.91(s,3H),0.59(d,J=4.8Hz,1H),0.36(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ170.4,170.2,85.5,83.1,81.3,77.8,75.8,70.7,57.5,49.7,46.4,46.3,45.5,45.1,41.2,37.3,33.1,32.3,31.7,30.2,29.2,28.6,27.0,26.6,26.2,26.0,22.8,22.5,21.8,21.6,21.5,20.6,20.3,20.0,15.1;HRMS(ESI)calcd for C36H57O8[M+H]+617.4048,found617.4048.
(4):3位羟基糖苷化产物6的合成
在氮气保护下,将化合物4(12mg,0.02mmol)和木糖炔酯给体5(25mg,0.04mmol)溶于干燥的二氯甲烷(2.5ml)中,并加入4A分子筛,在室温下搅拌半个小时再加入催化剂Ph3PAuNTf2(8mg,0.01mmol)继续在室温下搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物18(22mg,92%):[α]D 25=29.4(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ8.01-7.94(m,6H),7.56-7.47(m,3H),7.40-7.31(m,6H),5.78(t,J=7.6Hz,1H),5.45(dd,J=5.6,7.6Hz,1H),5.34-5.28(m,2H),4.85(d,J=5.6Hz,1H),4.64(td,J=4.4,8.8Hz,1H),4.46(dd,J=4.4,12.0Hz,1H),4.02(t,J=7.2Hz,1H),3.68(dd,J=7.6,12.0Hz,1H),3.25(dd,J=4.4,11.6Hz,1H),2.42(d,J=8.0Hz,1H),2.00(s,3H),1.96(s,3H),1.90(s,3H),1.43(s,3H),1.41(s,3H),1.32(s,3H),1.30(s,3H),0.95(s,3H),0.80(s,3H),0.78(s,3H),0.55(d,J=4.4Hz,1H),0.34(d,J=4.4Hz,1H);13C NMR(100MHz,CDCl3)δ170.5,170.3(2C),165.6,165.5,165.2,133.4,133.3,133.2,129.9,129.8,129.4,129.2,129.1,128.4(2C),128.3,102.5,88.3,85.6,83.1,81.2,75.8,70.8,70.7,70.3,69.5,61.5,57.4,49.7,46.4,46.3,45.4,44.6,41.5,37.2,32.8,32.3,31.6,29.7,28.9,28.8,28.1,27.1,26.2,26.0,22.8,22.6,21.8,21.6,20.6,20.2,20.0,15.8;HRMS(ESI)calcd for C62H80O15N[M+NH4]+1078.55225,found 1078.55305.
(5):膜荚黄芪皂苷Ⅱ的合成
在氮气保护下,将化合物6(50mg,0.047mmol)溶于干燥的甲醇(3ml)中,再加入甲醇钠(0.329mmol),室温下搅拌直到TLC跟踪显示原料反应完全,先用酸性树脂中和PH至中性偏酸性,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物膜荚黄芪皂苷Ⅱ(25.3mg,86%):[α]D 25=57.2(c=0.5,CH3OH);1H NMR(400MHz,C5D5N)δ6.55(bs,1H),5.68(bs,1H),5.05(dd,J=6.8,14.0Hz,1H),4.93(d,J=7.2Hz,1H);4.40(dd,J=4.8,11.2Hz,1H),4.27-4.22(m,1H),4.19(t,J=8.4Hz,1H),4.09-4.05(m,1H),3.91(dd,J=5.6,8.8Hz,1H),3.81-3.72(m,2H),3.66(dd,J=4.0,11.6Hz,1H),3.15(dd,J=10.8,20.4Hz,1H),2.55(d,J=7.6Hz,1H),2.45-2.42(m,1H),2.35-2.28(m,1H),2.00(s,3H),1.58(s,3H),1.43(s,3H),1.34(s,3H),1.32(s,3H),1.30(s,3H),1.01(s,3H);0.58(d,J=4.0Hz,1H),0.30(d,J=4.0Hz,1H);13C NMR(100MHz,C5D5N)δ107.4,88.5,87.0,81.5,78.3,75.4,73.2,71.0,67.8,66.8,58.1,53.8,46.8,46.4,45.9,44.8,42.5,38.4,34.7,33.2,32.3,30.4,30.1,29.3,28.7,28.3,28.0,26.9,26.2,26.0,21.3,20.8,20.0,16.4;HRMS(ESI)calcd forC35H58O9Na[M+Na]+645.3973,found 645.3974.
实施例2:
(1)3位羟基保护的环黄芪醇衍生物3的合成
在氮气保护下,将环黄芪醇(400mg,0.82mmol)溶于干燥的DMF(0.6 6mL)再向体系中加入TBSCl(245mg,1.63mmol),咪唑(222mg,3.27mmol),在室温搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物2(343.2mg,70%):
(2):全羟基保护的环黄芪醇衍生物3的合成
在氮气保护,0摄氏度条件下,化合物2(133mg,0.22mmol),PPy(58mg,0.44mmol)溶于干燥的甲苯(0.44ml)中,再向体系中加入乙酸酐(0.27ml,3.3mmol),DIPEA(0.639ml,4.4mmol),体系缓慢升至室温然后在加热到105摄氏度,搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物3(139.7mg,99%)。
(3):3位羟基裸露的环黄芪醇衍生物4的合成
在氮气保护下,将化合物3(20mg,0.03mmol)溶于干燥的甲醇(0.6mL)中,在室温下加入樟脑磺酸(19mg,0.09mmol),搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物4(14mg,83%)。
(4):3位羟基糖苷化产物6的合成
在氮气保护下,将化合物4(12mg,0.02mmol)和木糖炔酯给体5(12.5mg,0.02mmol)溶于干燥的二氯甲烷(2ml)中,并加入4A分子筛,在室温下搅拌半个小时再加入催化剂Ph3PAuNTf2(1.6mg,0.002mmol)继续在室温下搅拌直到TLC跟踪显示原料反应完全,减压浓缩粗产品,然后柱层析得到白色固体化合物18(21mg,88%).
(5):膜荚黄芪皂苷Ⅱ的合成
在氮气保护下,将化合物6(50mg,0.047mmol)溶于干燥的甲醇(4.7ml)中,再加入甲醇钠(0.47mmol),室温下搅拌直到TLC跟踪显示原料反应完全,先用酸性树脂中和PH至中性偏酸性,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物膜荚黄芪皂苷Ⅱ(25.3mg,86%)。
对比例1:步骤(1)中,保护基使用常规当量,3-OH不能完全被保护。
在氮气保护下,将环黄芪醇(400mg,0.82mmol)溶于干燥的DMF(0.6mL)再向体系中加入TBSCl(147mg,0.98mmol),咪唑(111mg,1.64mmol),在室温搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到白色固体化合物2(196mg,40%)。
对比例2:步骤(1)中,低浓度下,25-OH不能被乙酰化。
在氮气保护,0℃条件下,环黄芪醇(180mg,0.37mmol),PPy(108mg,0.74mmol)溶于干燥的甲苯(10mL)中,再向体系中加入乙酸酐(348μL,3.67mmol),DIPEA(912μL,5.55mmol),体系缓慢升至室温然后在加热到105℃,搅拌直到TLC跟踪显示原料反应完全,将反应体系用乙酸乙酯萃取,并依次用1mol/l HCl、饱和碳酸氢钠、饱和NaCl洗,无水硫酸钠干燥,抽滤,减压浓缩粗产品,然后柱层析得到25-OH不能被乙酰化的白色固体化合物(184mg,81.3%):[α]D25=73.5(c=1,CHCl3);1H NMR(400MHz,CDCl3)δ5.44-5.39(m,1H),4.75(td,J=4.4,9.2Hz,1H),4.60(dd,J=4.4,11.2Hz,1H),3.72(dd,J=6.8,8.4Hz,1H),2.50(d,J=8.4Hz,1H),2.38(td,J=5.2,11.6Hz,1H),2.17(dd,J=8.0,13.6Hz,1H),2.05(s,3H),2.02(s,3H),1.99(s,3H),1.30(s,3H),1.29(s,3H),1.20(s,3H),1.09(s,3H),0.99(s,3H),0.98(s,3H),0.85(s,3H),0.61(d,J=4.8Hz,1H),0.38(d,J=4.8Hz,1H);13C NMR(100MHz,CDCl3)δ170.8,170.6,170.4,85.6,81.9,79.5,75.6,70.9,70.2,57.1,49.7,46.2,46.1,45.3,45.0,40.1,36.5,32.9,32.5,31.4,29.7,29.2,28.4,27.8,27.7,26.6,26.0(2C),24.5,21.8,21.6,21.2,20.7,20.4,20.0,16.2;HRMS(ESI)calcd for C36H57O8[M+H]+617.4048,found 617.4049.
对比例3:步骤(3)中,常规TBS脱保护的不能得到化合物4。
在氮气保护,0℃条件下,环黄芪醇3位TBS保护,6、16位Piv保护,25位接全Bz保护的葡萄糖的化合物(15mg,0.011mmol),溶于干燥的四氢呋喃(1.5mL)中,再向体系中加入醋酸(3μL,0.055mmol),然后再加入TBAF(4.31mg,0.0165mmol),体系缓慢升至室温,搅拌,TLC跟踪显示原料一直未反应。
在氮气保护,0℃条件下,环黄芪醇3位TBS保护,6、16位Piv保护,25位接全Bz保护的葡萄糖的化合物(10mg,0.0074mmol),溶于干燥的甲醇(0.4mL)中,再向体系中加入70%HF·Py(30μL),搅拌,体系缓慢升至室温,TLC跟踪显示原料一直未反应。
Claims (7)
1.一种膜荚黄芪皂苷Ⅱ的合成方法,其特征在于,包括以下步骤:
(1)3位羟基选择性保护:将环黄芪醇溶于第一溶剂中,在碱性条件下,与硅基化试剂作用反应,得到3位羟基选择性保护的化合物2;
(2)6,16,25位羟基选择性保护:0℃以下,将化合物2和PPy溶于第二溶剂中,再加入酸酐和DIPEA,将反应温度缓慢升至室温后再加热到100~120℃,继续反应直到TLC跟踪显示反应完全,得到6,16,25位羟基保护的化合物3;
(3)选择性脱除3位羟基:将化合物3溶于第三溶剂中,酸性条件下脱除3位保护基,得到化合物4;
(4)构建3位糖苷键:将化合物4和木糖炔酯给体5溶于第四溶剂中,并加入干燥剂,在室温下搅拌后,加入催化剂,继续在室温下反应直到TLC跟踪显示化合物4反应完全为止,得到化合物6;
(5)最终脱保护:在碱性条件下,第五溶剂中,将化合物6的所有保护基脱除,即得膜荚黄芪皂苷Ⅱ,
其中,所述R1选自TBS或TBDPS;所述R2选自乙酰基、丙酰基、丁酰基或异丙酰基;所述R3选自苯甲酰基、对甲基苯甲酰基或邻甲基苯甲酰基;X选自以下基团之一:
步骤(2)中,所述第二溶剂为甲苯或1,2-二氯乙烷;所述化合物2在所述第二溶剂中的浓度为0.1~5mol/L;所述酸酐选自乙酸酐、丙酸酐、丁酸酐或异丙酸酐,所述化合物2、PPy、酸酐和DIPEA的摩尔比为1:1.5:8:12~1:2:15:20;
步骤(3)中,所述第三溶剂为甲醇,化合物3在所述第三溶剂中的浓度为0.014~0.5mol/L;所述酸为樟脑磺酸,所述化合物3和樟脑磺酸的摩尔比为1:3~1:4。
2.根据权利要求1所述的方法,其特征在于,步骤(1)中,所述第一溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种;所述化合物1在所述第一溶剂中的浓度为0.1~1.5mol/L。
3.根据权利要求1所述的方法,其特征在于,步骤(1)中,所述硅基化试剂选自TBSCl,所述碱选自三乙胺、咪唑或二异丙基乙基胺中的一种或多种,化合物1、所述硅基化试剂和所述碱的摩尔比为1:1.5:2~1:4:6。
4.根据权利要求1所述的方法,其特征在于,步骤(4)中,所述催化剂选自一价金的络合物;所述干燥剂选自分子筛;化合物4、木糖炔酯给体5和催化剂的摩尔比为1:1:0.1~1:5:0.8。
5.根据权利要求1所述的方法,其特征在于,步骤(4)中,所述第四溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述化合物4在第四溶剂中的浓度为0.001~1mol/L。
6.根据权利要求1所述的方法,其特征在于,步骤(5)中,所述碱选自甲醇钠、氢氧化钠、碳酸钾、氢氧化钾;所述化合物6和所述碱的摩尔比为1:7~20。
7.根据权利要求1所述的合成方法,其特征在于,步骤(5)中,所述第五溶剂选自二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷、DMF、甲苯、苯、二氧六环、吡啶、冰醋酸、四氢呋喃、三乙胺、乙酸乙酯、丙酮、甲醇、乙醇、DMSO或***中的一种或多种,所述化合物6在第五溶剂中的浓度为0.001~1mol/L。
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