CN108250206B - 一种联芳木脂素类化合物及其中间体的合成方法 - Google Patents
一种联芳木脂素类化合物及其中间体的合成方法 Download PDFInfo
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- CN108250206B CN108250206B CN201810052151.XA CN201810052151A CN108250206B CN 108250206 B CN108250206 B CN 108250206B CN 201810052151 A CN201810052151 A CN 201810052151A CN 108250206 B CN108250206 B CN 108250206B
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- Prior art keywords
- biaryl
- alkynyl
- aldehyde
- follows
- lignan
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- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- JDZNTUQRMDAIRO-UHFFFAOYSA-N dimethylmyleran Chemical compound CS(=O)(=O)OC(C)CCC(C)OS(C)(=O)=O JDZNTUQRMDAIRO-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229930182790 isoschizandrin Natural products 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000037830 nasal cancer Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
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Abstract
本发明公开了一种高对映体选择性合成联芳木脂素(+)‑Isoschizandrin和(+)‑Steganone的方法，在钯催化剂催化下，联芳基醛与炔基溴在银盐和添加剂，氨基酸的存在下发生反应，反应结束后经过后处理得到所述的炔基化产物；所得的高对映体选择性的炔基化产物经过后续官能团化能够合成(+)‑Isoschizandrin和(+)‑Steganone的中间体；本发明操作条件简单，条件温和，步骤简短；反应底物的产率和对映体选择性较高，在转化过程中对映体选择性不降低。
Description
技术领域
本发明涉及一种高对映体选择性合成联芳木脂素(+)-Isoschizandrin和(+)-Steganone的方法，属于天然分子的合成领域。
背景技术
轴手性联芳结构广泛存在于天然产物、药物和先进材料中。并且常用的手性催化剂如联萘芳结构的手性二醇、手性磷酸都具有轴手性联芳结构，这些轴手性化合物在不对称合成中都具有非常重要的地位。目前，约有100种联芳木脂素从五味子类植物中分离出来；由于联芳环戊二烯木脂素具有独特的轴手性结构和重要的生理活性，化学家们对其越来越感兴趣，并把这类结构作为合成目标，参见a)R.S.Ward,Nat.Prod.Rep.1990,7,349；b)J.Chang,J.Reiner,J.Xie,Chem.Rev.2005,105,4581；c)G.Bringmann,T.Gulder,T.A.M.Gulder,M.Breuning,Chem.Rev.2011,111,563；
表1.联芳环戊二烯木脂素类天然分子
近年来，一些文献报道了不同条件下合成联芳环戊二烯木脂素结构的天然产物(表1)，例如(+)-isoschizandrin和其衍生物起源于中国北方的五味子，被中医和日本传统医学作为镇咳和滋补品，参见a)D.A.Whiting,Nat.Prod.Rep.1985,2,191；b)D.A.Whiting,Nat.Prod.Rep.1987,4,499；(-)-steganone和其衍生物起源于Steganotaenia araliacea，在老鼠中对P-338型白血病具有很好的活性，同时对人体鼻癌细胞也具有很好的活性，参见S.M.Kupchan,R.W.Britton,M.F.Zeigler,C.J.Gilmore,R.J.Restivo,R.F.Bryan,J.Am.Chem.Soc.1973,95,1335.；正是由于其具有非常重要的活性，很多方法被应用于这类结构的全合成之中，isoschizandrin的全合成参加a)Takeya,T.；Ohguchi,A.；Tobinaga,S.Chem.Pharm.Bull.1994,42,438；b)G.A.Molander,K.M.George,L.G.MonovichJ.Org.Chem.2003,68,9533；c)W.-W.Chen,Q.Zhao,M.-H.Xu,G.-Q.Lin,Org.Lett.2010,12,1072；d)K.Mori,T.Itakura,T.Akiyama,Angew.Chem.Int.Ed.2016,55,11642.e)M.Tanaka,C.Mukaiyama,H.Mitsuhashi,M.Maruno,T Wakamatsu,J.Org.Chem.1995,60,4339；Steganone的全合成,参见a)A.I.Meyers,J.R.Flisak,R.A.Aitken,J.Am.Chem.Soc.1987,109,5446.b)L.G.Monovich,Y.L.Hue′rou,M.
G.A.Molander,J.Am.Chem.Soc.2000,122,52；c)R.S.Coleman,S.R.Gurrala,S.Mitra,A.Raao,J.Org.Chem.2005,70,8932；d)P.Magnus,J.Schultz,T.Gallagher,J.Am.Chem.Soc.1985,107,4984.e)R.Dhal,J.P.Robin,E.Brown,Tetrahedron 1983,39,2787.f)M.Mervic,Y.Ben-David,E.Ghera,Tetrahedron Lett.1981,22,5091.g)F.E.Ziegler,I.C.Chliwner,K.W.Fowler,S.J.Kanfer,S.J.Kuo,N.D.Sinha,J.Am.Chem.Soc.1980,102,790.h)E.Brown,R.Dhal,J.P.Robin,Tetrahedron Lett.1979,20,733.i)E.R.Larson,R.A.Raphael,TetrahedronLett.1979,20,5041.j)D.Becker,L.R.Hughes,R.A.Raphael,J.Chem.Soc.,PerkinTrans.1977,1,1674.k)L.R.Hughes,R.A.Raphael,Tetrahedron Lett.1976,17,1543.l)A.S.Kende,L.S.Liebeskind,J.Am.Chem.Soc.1976,98,267.m)Tomioka,K.；Ishiguro,T.；Iitaka,Y.；Koga,K.Tetrahedron 1984,40,1303.n)E.R.Larson,R.A.Raphael,J.Chem.Soc.,Perkin Trans.1982,1,521.o)Robin,J.P.；Gringgore,O.；Brown,E.Tetrahedron Lett.1980,21,2709.p)M.Uemura,A.Daimon,Y.Hayashi,J.Chem.Soc.,Chem.Commun.1995,19,1943。尽管这些合成方法能够构筑联芳环戊二烯木脂素结构的天然分子，但也存在一定的问题，如较低的立体控制及冗长的合成步骤、较少的合成量。基于此，我们发展了氨基酸作为瞬态导向基来构筑轴手性化合物，利用钯催化不对称炔基化作为核心步骤完成了(+)-Isoschizandrin和(+)-Steganone的形式合成，其对天然产物的合成以及新药筛选等都有重要意义。
发明内容
本发明的目的是提供一种反应条件温和、步骤简短、产物产率和对映体选择性较高的(+)-Isoschizandrin和(+)-Steganone及其中间体的高效合成方法。
一种联芳木脂素中间体的合成方法，包括以下步骤：在钯催化剂催化下，联芳基醛与炔基溴在银盐和添加剂，氨基酸的存在下发生反应，反应结束后经过后处理得到高对映体选择性的联芳木脂素中间体；
所述的联芳木脂素中间体的结构如式(I)所示：
所述的联芳基醛的结构如式(II)所示：
式(I)～(II)中，R1为H或甲氧基；
R2和R3独立地选择H、甲氧基或者R2、R3与同其相连的C共同形成五元环。
作为优选，所述的联芳木脂素中间体的结构如式(I-1)或式(I-2)所示：
作为优选，所述的钯催化剂为醋酸钯，添加剂为磷酸二氢钾，所述的银盐为三氟乙酸银，所述的有机溶剂为醋酸、所述的氨基酸为手性纯的叔亮氨酸，所述的炔为三异丙基硅乙炔溴，反应温度为55℃，反应时间为48～58小时；联芳、保护的炔基溴、钯催化剂、添加剂、氨基酸和银盐的摩尔比为1：1.5～3：0.1：2：0.3：2。
本发明还提供了一种联芳木脂素类化合物的合成方法，包括以下步骤：
(1)按照权利要求1～3任一项所述的方法得到联芳木脂素中间体；
(2)步骤(1)得到的联芳木脂素中间体经过后续官能团化得到所述的联芳木脂素类化合物；
所述的联芳木脂素类化合物为(+)-Isoschizandrin或(+)-Steganone以及他们的类似物；
作为优选，所述的联芳木脂素类化合物为(+)-Isoschizandrin，该方法包括以下步骤：
(1)炔基的引入：以联芳为原料，加入磷酸二氢钾，三异丙基硅乙炔溴，三氟乙酸银，醋酸、手性纯的叔亮氨酸，在醋酸钯催化下反应温度为55℃，反应时间为48～58小时，然后后处理，柱色谱纯化可以得到炔基化的联芳基醛；
(2)醛的保护：使用催化量的对甲苯磺酸，原甲酸三甲酯为溶剂，在室温条件下反应24h,得到保护后的联芳化合物；
(3)硅基的脱除与甲基的引入：加入TBAF脱除硅基后，快速后处理得到端炔粗产物，在-78℃下加入正丁基锂反应2小时后加入碘甲烷得到目标联芳化合物；
(4)炔基的顺式还原：Ti(OiPr)4/iPrMgBr条件下还原炔成顺式烯烃；
(5)脱除保护基得到目标化合物：使用稀盐酸将保护基脱除得到(+)-Isoschizandrin；
(6)中间体通过文献可以转化为目标分子(+)-isoschizandrin(G.A.Molander,K.M.George,L.G.Monovich J.Org.Chem.2003,68,9533)。
作为优选，所述的联芳木脂素类化合物为(+)-Steganone，该方法包括以下步骤：
(1)炔基的引入：以联芳为原料，加入磷酸二氢钾，三氟乙酸银，醋酸、手性纯的叔亮氨酸，在醋酸钯催化下反应温度为55℃，反应时间为48～58小时，然后后处理，柱色谱纯化可以得到炔基化的联芳基醛；
(2)Knoevenagel缩合引入侧链：使用丙二酸二甲酯，在脯氨酸催化下发生Knoevenagel缩合反应；
(3)烯烃的还原：Ni(Rany)还原得到烯烃还原后的产物；
(4)硅基的脱除与溴代：TBAF条件下脱除硅基，后处理后的粗产物在AgNO3/NBS条件下得到溴代产物；
(5)炔烃的水合：Hg(OTf)2/AgSbF6条件下，以二氯甲烷、水、甲醇作为溶剂得到水合后的产物；
(6)关环得到(+)-Steganone的中间体；
(7)中间体通过文献可以转化为目标分子(+)-Steganone(A.I.Meyers,J.R.Flisak,R.A.Aitken,J.Am.Chem.Soc.1987,109,5446)。
同现有技术相比，本发明的有益效果体现在：
(1)操作条件简单，条件温和，步骤简短；
(2)反应底物的产率和对映体选择性较高；
(3)反应立体选择性强，通过氨基酸手性控制，可以使产物具有很高的ee值，在转化过程中对映体选择性不降低。
附图说明
图1为化合物11的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝99/1,rate＝0.5mL/min,220nm；
图2为化合物13的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝95/5,rate＝0.8mL/min,220nm
图3为化合物15的HPLC图谱，色谱条件为：AS-H/AS-H,Hex/iPrOH＝95/5,rate＝0.30mL/min,220nm
图4为化合物17的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝95/5,rate＝0.5mL/min,220nm
图5为化合物18的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝80/20,rate＝0.8mL/min,220nm
图6为化合物19的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝80/20,rate＝0.8mL/min,220nm
图7为化合物20的HPLC图谱，色谱条件为：AD-H,Hex/iPrOH＝60/40,rate＝1.0mL/min,220nm。
具体实施方式
实施例1
合成(+)-isoschizandrin.的反应路线如下：
反应条件：(a)Pd(OAc)2,L1,AgTFA,KH2PO4,2a,HOAc,55℃,58h,N2,85％；(b)TsOH,trimethyl orthoformate；(c)TBAF,THF,rt；(d)n-BuLi,MeI,THF,-78℃,91％for 3steps；(e)Ti(iOPr)4,iPrMgCl,Et2O,-78℃ to-45℃；(f)H2O,1M HCl,rt,88％for 2steps.DME＝dimethoxyethane.
(1)化合物11：在250mL的希莱克管中加入底物10(1.81g,5.0mmol),TIPS-保护的炔溴2a(15.0mmol),Pd(OAc)2(112.3mg,0.50mmol),L-叔亮氨酸(196.8mg,1.50mmol),AgTFA(2.21g,10.0mmol),KH2PO4(2.73g,10.0mmol),HOAc(40mL).管内置换氮气,55℃下反应58小时。冷却到室温，用乙酸乙酯稀释后用硅藻土过滤，滤液浓缩后用饱和碳酸氢钠淬灭(60mL)，并且用乙酸乙酯萃取(3×40mL).将合并有机相，用无水硫酸钠干燥，过滤，浓缩；所得的粗产物进行柱层析(石油醚/乙酸乙酯,6:1),得到淡黄色油状物11 2.30g,85％,98％ee).1H NMR(400MHz,CDCl3)δ9.59(s,1H),7.34(s,1H),6.87(s,1H),3.96(s,3H),3.93(s,6H),3.90(s,3H),3.70(s,3H),3.67(s,3H),0.88(s,21H).13C NMR(101MHz,CDCl3)δ190.93,153.47,153.45,152.33,151.73,147.80,143.33,130.21,129.83,123.79,120.07,111.05,105.26,105.08,94.37,61.16,61.09,61.04,60.87,56.24,56.22,18.59,18.58,11.20.HRMS(EI-TOF)calcd for C30H42O7Si(M+):542.2700,found:542.2698；Enantiomericexcess was determined by HPLC with a Daicel Chiralpak AD-H,图1，正己烷/异丙醇＝99/1,v＝0.5mL·min-1,λ＝220nm,t(minor)＝19.1min,t(major)＝22.3min,98％ee；[α]D 20＝+40.4(c＝1.0,CHCl3).
(2)化合物12：在100毫升烧瓶中加入11(2.30g,4.25mmol),TsOH(37.9mg,0.22mmol),原甲酸三甲酯(20ml).反应12小时,然后用饱和碳酸氢钠淬灭(20mL)，乙酸乙酯萃取(3×30mL).合并有机相并用硫酸钠干燥,过滤,浓缩.将其溶于四氢呋喃中(20ml),室温下加入四丁基氟化氨(1M in THF,6.4ml).一小时后,反应混合物加入水淬灭(20mL)，并且用乙酸乙酯萃取(3×30mL).合并后的有机相水洗(40ml)，硫酸钠干燥，浓缩。将其溶解在无水四氢呋喃中(20ml)，冷却到-78℃。加入正丁基锂(2.5M in hexanes,4.3mL)。反应1小时后，加入碘甲烷(0.69mL,1,57g,11mmol)，撤走低温。在反应混合中加入饱和氯化氨溶液(20mL).加入乙酸乙酯(50mL)萃取后，有机相用饱和氯化钠洗，硫酸钠干燥，浓缩。柱层析得到淡黄色油状12(1.71g,91％).1H NMR(400MHz,CDCl3)δ6.98(s,1H),6.79(s,1H),4.85(s,1H),3.91(s,3H),3.86(s,9H),3.69(s,3H),3.65(s,3H),1.75(s,3H).13C NMR(101MHz,CDCl3)δ152.78,152.57,151.98,151.58,142.33,142.00,132.86,125.61,123.62,119.87,110.41,104.51,102.44,87.92,78.90,60.91,60.89,60.79,60.48,55.93,55.90,54.90,53.70,4.24.HRMS(EI-TOF)calcd for C24H30O8(M+):446.1935,found:446.1942；
(3)化合物13:四异丙醇钛(5.7ml,19.1mmol)和醛12(1.71g,3.82mmol)溶于无水乙醚中(30ml).在-78℃下，反应两小时后慢慢滴入异丙基溴化镁(2.0M in diethylether,28.7mL)。反应4小时后缓慢升温至-45℃,12小时后撤出低温,加入水淬灭(20ml)，室温搅拌两小时。乙酸乙酯萃取(3×30mL)，有机相用硫酸钠干燥，过滤，旋干。将粗产物溶于丙酮(40ml)，加入稀盐酸(1M,40mL).2小时后,浓缩，乙酸乙酯萃取(3x 50mL).有机相用饱和食盐水洗(50mL)，硫酸钠干燥，旋干，柱层析得到醛13(1.35g,88％,98％ee).1H NMR(400MHz,CDCl3)δ9.41(s,1H),7.25(s,1H),6.64(s,1H),5.80(dd,J＝11.5,1.7Hz,1H),5.49(dq,J＝11.6,7.0Hz,1H),3.90(s,3H),3.87(s,3H),3.84(s,3H),3.83(s,3H),1.71(dd,J＝7.1,1.6Hz,3H).13C NMR(101MHz,CDCl3)δ191.37,153.18,152.94,152.03,151.42,147.61,140.84,133.22,129.87,129.29,128.84,127.21,119.21,108.36,104.73,60.98,60.95,60.66,60.64,56.02,56.01,14.47.HRMS(EI-TOF)calcd for C22H26O7(M+):402.1673,found:402.1682；Enantiomeric excess was determined by HPLC with aDaicel Chiralpak AD-H,图2，正己烷/异丙醇＝95/5,v＝0.8mL·min-1,λ＝220nm,t(minor)＝9.1min,t(major)＝11.2min,98％ee；[α]D 20＝+66.7(c＝1.0,CHCl3).
(4)(+)-isoschizandrin的合成：化合物13通过文献可以转化为目标分子(+)-isoschizandrin，参见：ref)G.A.Molander,K.M.George,L.G.Monovich J.Org.Chem.2003,68,9533
实施例2
合成(+)-steganone.的反应路线如下：
反应条件：(a)Pd(OAc)2,L1,AgTFA,KH2PO4,2a,HOAc,55℃,48h,N2,68％；(b)L-Proline,DMM,DMSO,Et3N,rt,94％；(c)Raney-Ni,H2,THF,rt,100％；(d)TBAF,THF 0℃；(e)AgNO3,NBS,acetone,0℃ 91％for 3steps；(f)Hg(OTf)2,AgSbF6,CH3OH,DCM,H2O,rt,61％；(g)DBU,THF,rt,90％.DMM＝dimethyl malonate,DCM＝dichloromethane,DMSO＝dimethylsulfoxide,NBS＝N-bromosuccinimide,DBU＝1,8-Diazabicyclo[5.4.0]undec-7-ene.
(1)化合物15：在250mL的希莱克管中加入底物14(1.81g,5.0mmol),TIPS-保护的炔溴2a(7.5mmol),Pd(OAc)2(112.3mg,0.50mmol),L-叔亮氨酸(196.8mg,1.50mmol),AgTFA(2.21g,10.0mmol),KH2PO4(2.73g,10.0mmol),HOAc(40mL).管内置换氮气,55℃下反应48小时。冷却到室温，用乙酸乙酯稀释后用硅藻土过滤，滤液浓缩后用饱和碳酸氢钠淬灭(60mL)，并且用乙酸乙酯萃取(3×40mL).将合并有机相，用无水硫酸钠干燥，过滤，浓缩；所得的粗产物进行柱层析(石油醚/乙酸乙酯,6:1),得到淡黄色油状物15(3.40g,68％,98％ee,o:o’＝5.9:1)。1H NMR(400MHz,CDCl3)δ9.61(s,1H),7.33(s,1H),7.02(s,1H),6.77(s,1H),6.05(d,J＝1.7Hz,2H),3.98(s,3H),3.93(s,3H),3.68(s,3H),0.88(s,21H).13C NMR(101MHz,CDCl3)δ190.76,153.40,151.39,147.98,147.80,147.41,132.99,131.07,130.23,118.18,111.81,111.12,105.23,101.87,93.65,61.27,61.10,56.26,18.54,11.16.HRMS(EI-TOF)calcd for C28H36O6Si(M+):496.2276,found:496.2275；Enantiomericexcess was determined by HPLC with two Daicel Chiralpak AS-H,图3，n-hexane/2-propanol＝95/5,v＝0.3mL·min-1,λ＝220nm,t(minor)＝27.4min,t(major)＝32.3min,98％ee；[α]D 20＝-36.4(c＝0.50,CHCl3).
(2)化合物16：在100mL烧瓶中，底物15(3.40g,6.8mmol),L-脯氨酸(230.3mg,2.0mmol),丙二酸二甲酯(13.6mmol,1.56ml),DMSO(20ml),三乙胺(2ml).室温下反应24h。乙酸乙酯萃取EtOAc(10×60mL).有机相用无水硫酸钠干燥，过滤,浓缩，柱层析得到16(3.89g,94％,o:o’＝5.7:1).1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.01(s,1H),6.84(s,1H),6.59(s,1H),6.01(d,J＝4.4Hz,2H),3.90(s,3H),3.82(s,3H),3.79(s,3H),3.73(s,3H),3.67(s,3H),0.89(s,21H).13C NMR(101MHz,CDCl3)δ167.57,164.43,152.96,151.75,148.09,147.15,144.25,141.87,133.31,130.39,127.94,125.45,116.78,112.14,111.18,106.86,105.43,101.75,92.84,61.19,60.98,56.13,52.65,52.59,18.55,11.19.HRMS(ESI +)calcd for C33H43O9Si(M+H)+:611.2671,found:611.2680；[α]D 20＝-179.0(c＝1.00,CHCl3).
(3)化合物17:将16(6.39mmol)溶于30mL四氢呋喃溶液中，用0.5毫升Ni(Raney)(THF剧烈搅拌)，用氢气球将体系内其他置换为氢气，室温下进行氢化。1小时后,将反应混合物用硅藻土过滤，浓缩得到目标产物(>99％,98％ee,o:o’＝5.7:1).1H NMR(400MHz,CDCl3)δ7.00(s,1H),6.65(s,1H),6.55(s,1H),6.01(d,J＝7.4Hz,2H),3.84(s,3H),3.82(s,3H),3.64(s,3H),3.63(s,3H),3.61(s,3H),0.90(s,21H).13C NMR(101MHz,CDCl3)δ169.56,169.37,152.76,151.63,148.00,146.79,141.17,134.60,132.37,127.91,117.12,112.24,110.90,108.98,105.69,101.64,92.08,61.10,60.91,56.16,52.57,52.51,52.44,32.44,18.57,11.22.HRMS(ESI+)calcd for C33H45O9Si(M+H)+:613.2827,found:613.2828；Enantiomeric excess was determined by HPLC with a Daicel Chiralpak AD-H,图4，正己烷/异丙醇＝95/5,v＝0.5mL·min-1,λ＝220nm,t(minor)＝9.3min,t(major)＝10.9min,98％ee；
(4)化合物18：在100ml烧瓶中,17(2.89g,4.72mmol)溶于四氢呋喃(20ml)中，在0℃下加入四丁基氟化氨(1M in THF,9.6ml).2小时后,加入水淬灭(20mL)，乙酸乙酯萃取(3×40mL).有机相用水(40ml)洗后，无水硫酸钠干燥，，过滤，旋干。将其溶于丙酮(20ml)中，冷却到0℃。加入AgNO3(320.7mg,1.89mmol)反应1小时，NBS(1.0g)的丙酮溶液(10ml)在5小时内缓慢加入。再反应3小时，反应混合物用硅藻土过滤，柱层析得到目标产物18(2.30g,91％,97％ee,o:o’＝8.9:1)。1H NMR(400MHz,CDCl3)δ6.97(s,1H),6.63(s,1H),6.57(s,1H),6.03(d,J＝8.2Hz,2H),3.86(s,6H),3.68(s,3H),3.64(s,3H),3.64(s,3H),3.48(t,J＝7.8Hz,1H),3.02–2.90(m,2H).13C NMR(101MHz,CDCl3)δ169.58,169.35,152.86,151.82,148.37,146.87,140.99,135.10,131.79,127.16,116.48,112.01,110.75,108.61,101.80,79.14,61.22,60.99,56.09,52.67,52.64,52.27,51.03,32.48.HRMS(ESI+)calcd forC24H24O9Br(M+H)+:535.0598,found:535.0605；Enantiomeric excess was determined byHPLC with a Daicel Chiralpak AD-H,图5，n-hexane/2-propanol＝80/20,v＝0.8mL·min-1,λ＝220nm,t(minor)＝8.6min,t(major)＝17.0min,97％ee；[α]D 20＝+70.9(c＝1.00,CHCl3).
(5)化合物19：在100ml烧瓶中,加入18(2.30g,4.30mmol)，三氟甲磺酸汞(428.8mg),六氟锑酸银(1.48g),甲醇(10.0ml),二氯甲烷(10.0ml),水(1.0ml).室温下反应5小时，硅藻土过滤，旋干.柱层析得到19(1.45g,61％,95％ee)。1H NMR(400MHz,CDCl3)δ7.30(s,1H),6.64(s,1H),6.56(s,1H),6.09(d,J＝5.9Hz,2H),4.06(d,J＝13.5Hz,1H),3.94(d,J＝13.5Hz,1H),3.85(s,3H),3.83(s,3H),3.65(s,3H),3.63(s,3H),3.60(s,3H),3.48(t,J＝7.7Hz,1H),2.99(dd,J＝14.6,7.5Hz,1H),2.90(dd,J＝14.6,7.9Hz,1H).13CNMR(101MHz,CDCl3)δ192.20,169.22,153.32,150.89,150.80,147.41,141.07,132.01,131.31,130.66,127.14,111.83,109.48,108.36,102.29,60.99,60.88,56.04,52.76,52.74,51.90,34.61,32.08.HRMS(ESI+)calcd for C24H26O10Br(M+H)+:553.0705,found:553.0717；Enantiomeric excess was determined by HPLC with a Daicel ChiralpakAD-H,图6，n-hexane/2-propanol＝80/20,v＝0.8mL·min-1,λ＝220nm,t(minor)＝17.4min,t(major)＝21.8min,95％ee；[α]D 20＝-1.9(c＝1.0,CHCl3).
(6)化合物20：在100ml烧瓶中,19(1.43g,2.60mmol)溶于四氢呋喃中(20ml)，加入DBU(0.43ml,2.86mmol).反应在室温下搅拌30分钟后，硅藻土过滤旋干。得到20(1.11g,90％,96％ee)。1H NMR(400MHz,CDCl3)δ7.54(s,1H),6.62(s,1H),6.42(s,1H),6.06(s,1H),6.03(s,1H),3.89(s,3H),3.83(s,3H),3.77(s,3H),3.72(s,3H),3.54(s,3H),3.29(d,J＝13.8Hz,1H),3.18(d,J＝13.8Hz,1H),3.04(d,J＝13.8Hz,1H),2.74(d,J＝13.8Hz,1H).13CNMR(101MHz,CDCl3)δ196.46,170.66,170.30,153.42,151.73,151.16,147.89,141.88,132.54,132.33,130.58,127.77,112.64,108.94,107.54,102.15,61.33,61.17,59.07,56.06,53.27,53.13,45.20,36.41.HRMS(ESI+)calcd for C24H24O10(M+H)+:473.1442,found:473.1450；Enantiomeric excess was determined by HPLC with a DaicelChiralpak AD-H,图7，n-hexane/2-propanol＝60/40,v＝1.0mL·min-1,λ＝220nm,t(minor)＝9.3min,t(major)＝12.6min,96％ee；[α]D 20＝+69.2(c＝1.0,CHCl3).
(7)(+)-steganone的合成：化合物20通过文献可以转化为目标分子(+)-steganone，参见：ref)A.I.Meyers,J.R.Flisak,R.A.Aitken,J.Am.Chem.Soc.1987,109,5446。
Claims (4)
1.一种联芳木脂素中间体的合成方法，其特征在于，包括以下步骤：在钯催化剂催化下，联芳基醛与炔基溴在银盐和添加剂，氨基酸的存在下发生反应，反应结束后经过后处理得到高对映体选择性的联芳木脂素中间体；
所述的联芳木脂素中间体的结构如式（I）所示：
所述的联芳基醛的结构如式（II）所示：
式（I）~（II）中，R1为H或甲氧基；
R2和R3独立地选择H、甲氧基或者R2、R3与同其相连的C共同形成五元环；
所述的钯催化剂为醋酸钯，添加剂为磷酸二氢钾，所述的银盐为三氟乙酸银，所述的有机溶剂为醋酸、所述的氨基酸为手性纯的叔亮氨酸，所述的炔基溴为三异丙基硅乙炔溴，反应温度为55℃ ，反应时间为48～58小时；联芳基醛、炔基溴、钯催化剂、添加剂、氨基酸和银盐的摩尔比为1 ：1.5~3 ：0.1 ：2 ： 0.3 ：2。
2.根据权利要求1所述的联芳木脂素中间体的合成方法，其特征在于，所述的联芳木脂素中间体的结构如式（I-1）或式（I-2）所示：
3.一种联芳木脂素类化合物的合成方法，其特征在于，所述的联芳木脂素类化合物为(+)-Isoschizandrin，方法包括以下步骤：
(1) 炔基的引入：以联芳基醛为原料，加入磷酸二氢钾，三异丙基硅乙炔溴，三氟乙酸银，醋酸、手性纯的叔亮氨酸，在醋酸钯催化下反应，反应温度为55℃ ，反应时间为48～58小时，然后后处理，柱色谱纯化得到炔基化的联芳基醛；
所述的联芳基醛的结构式如下：
所述的炔基化的联芳基醛的结构式如下：
(2) 醛的保护、硅基的脱除与甲基的引入：使用催化量的对甲苯磺酸，原甲酸三甲酯为溶剂，所述的炔基化的联芳基醛在室温条件下反应24h,加入TBAF脱除硅基后，快速后处理得到端炔粗产物，在-78℃ 下加入正丁基锂反应2小时后加入碘甲烷得到目标联芳化合物；
所述的目标联芳化合物的结构式如下：
(3) 炔基的顺式还原和脱除保护基：Ti(OiPr)4/iPrMgBr条件下还原炔成顺式烯烃；再使用稀盐酸将保护基脱除得到(+)-Isoschizandrin的中间体；
所述的(+)-Isoschizandrin的中间体的结构式如下：
（4）中间体转化为目标分子(+)-Isoschizandrin；
所述的目标分子(+)-Isoschizandrin的结构式如下：
4.一种联芳木脂素类化合物的合成方法，其特征在于，所述的联芳木脂素类化合物为(+)-Steganone，方法包括以下步骤：
(1) 炔基的引入：以联芳基醛为原料，加入磷酸二氢钾，三氟乙酸银，醋酸、手性纯的叔亮氨酸，在醋酸钯催化下反应温度为55℃ ，反应时间为48～58小时，然后后处理，柱色谱纯化可以得到炔基化的联芳基醛；
所述的联芳基醛的结构式如下：
所述的炔基化的联芳基醛的结构式如下：
(2) Knoevenagel缩合引入侧链：使用丙二酸二甲酯，在脯氨酸催化下发生Knoevenagel缩合反应；
(3) 烯烃的还原：Ni(Rany)还原得到烯烃还原后的产物；
(4) 硅基的脱除与溴代：TBAF条件下脱除硅基，后处理后的粗产物在AgNO3/NBS条件下得到溴代产物；
所述的溴代产物的结构式如下：
(5) 炔烃的水合：Hg(OTf)2/AgSbF6条件下，以二氯甲烷、水、甲醇作为溶剂得到水合后的产物；
所述水合后的产物的结构式如下：
(6) 关环得到(+)-Steganone的中间体；
所述的(+)-Steganone的中间体的结构式如下：
(7) 中间体转化为目标分子(+)-Steganone；
所述的目标分子(+)-Steganone的结构式如下：
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| CN105820185A (zh) * | 2016-04-15 | 2016-08-03 | 浙江大学 | 一种β-硅基取代的氨基酸衍生物的合成方法 |
| US20170035829A1 (en) * | 2015-07-15 | 2017-02-09 | Unigen, Inc. | Compositions, Methods, and Medical Compositions for Treatment of and Maintaining the Health of the Liver |
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| US20170035829A1 (en) * | 2015-07-15 | 2017-02-09 | Unigen, Inc. | Compositions, Methods, and Medical Compositions for Treatment of and Maintaining the Health of the Liver |
| CN105820185A (zh) * | 2016-04-15 | 2016-08-03 | 浙江大学 | 一种β-硅基取代的氨基酸衍生物的合成方法 |
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| Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C-H Olefination Enabled by a Transient Chiral Auxiliary;Qi-JunYao等;《Angew.Chem》;20170504;第129卷;20170504 * |
| Highly regioselective meta arylation of oxalyl amide-protected β-arylethylamine via the Catellani reaction;Jian Han等;《ChemComm》;20160427;第52卷(第42期);第6905页scheme2 * |
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