CN114031612A - (±)-Nicotlactone A及其差向异构体的合成方法 - Google Patents
(±)-Nicotlactone A及其差向异构体的合成方法 Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims description 5
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
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- 229940125898 compound 5 Drugs 0.000 claims description 3
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- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 3
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003638 chemical reducing agent Substances 0.000 claims description 2
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- 229910052738 indium Inorganic materials 0.000 claims description 2
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- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- BDONGWCKHZIYMP-UHFFFAOYSA-N n-[bis(dimethylamino)phosphoryl]-n-methylmethanamine;hydrogen peroxide;oxomolybdenum;piperidin-1-ide Chemical compound OO.OO.[Mo]=O.C1CC[N-]CC1.CN(C)P(=O)(N(C)C)N(C)C BDONGWCKHZIYMP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 9
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- -1 Lignan compound Chemical class 0.000 description 2
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- AMNAZJFEONUVTD-KEWDHRJRSA-N (2s,3s,4s,5r,6r)-6-(4-amino-2-oxopyrimidin-1-yl)-4,5-dihydroxy-3-[[(2s)-3-hydroxy-2-[[2-(methylamino)acetyl]amino]propanoyl]amino]oxane-2-carboxamide Chemical compound O1[C@H](C(N)=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CNC)[C@H](O)[C@@H](O)[C@@H]1N1C(=O)N=C(N)C=C1 AMNAZJFEONUVTD-KEWDHRJRSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical group O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
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- 238000010746 Mukaiyama hydration reaction Methods 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
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- XLSMFKSTNGKWQX-UHFFFAOYSA-N hydroxyacetone Chemical compound CC(=O)CO XLSMFKSTNGKWQX-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000005692 lignans Chemical class 0.000 description 1
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 239000012044 organic layer Substances 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
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- 238000006257 total synthesis reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明提供制备具有抗烟草花叶病毒活性天然产物(±)‑Nicotlactone A及其差向异构体的合成方法,具体涉及用于制备(±)‑Nicotlactone A及其差向异构体的中间体以及制备这些中间体方法。本发明提供具有抗烟草花叶病毒活性天然产物(±)‑Nicotlactone A及其差向异构体的合成方法,该合成方法过程简单、高效,操作方便,条件温和。
Description
技术领域
本发明涉及有机合成技术领域,尤其是一种具有抗烟草花叶病毒活性天然产物(±)-Nicotlactone A及其差向异构体的合成方法。
背景技术
Nicotlactone A(1)是高雪梅等人从烟草(Nicotiana Tabacum)中分离鉴定的木脂素类化合物,其核心骨架含有γ-丁内酯结构,据文献报道该天然产物具有较高的抗病毒活性,在20μM浓度下对烟草花叶病毒的抑制率达到58.4%,优于对照药剂宁南霉素、病毒唑等(Gao,X.,Li,X.,&Yang,X.(2012).Lignan derivatives fromthe leaves Nicotianatabacum andtheir activities.Heterocycles,85(1),147-153.),可以作为先导化合物进行绿色抗病毒药物的创制。
关于Nicotlactone A(1)的合成,目前只有Krishna等人报道,该课题组以1-羟基丙烷-2-酮为原料,经Wittig反应、Sharpless环氧化、开环、双羟基化、酸催化等11步合成化合物(+)-Nicotlactone A(Krishna,P.R.,Prabhakar,S.,&Sravanthi,C.(2013).Thefirst stereoselective total synthesis ofnicotlactone A.Tetrahedron Letters,54(7),669-671.),合成路线如下。该合成路线使用较多保护基,步骤较长,不利于大量合成,严重限制了其作为先导化合物进行药物的开发,因此,开发Nicotlactone A及其类似物的简洁高效合成路线对于新型抗植物病毒药剂的创制具有十分重要的意义。
发明内容
本发明解决的技术问题是提供一种抗烟草花叶病毒活性天然产物(±)-Nicotlactone A(1)及其差向异构体的合成方法,该合成方法过程简单、高效、操作方便、条件温和。
本发明解决其技术问题所采用的技术方案是:一种(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法,该合成反应方程式如下:
其中,(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成路线1如下:
(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成路线2如下:
进一步地,这种(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法,具体包括如下步骤:
步骤1~3、化合物3的合成,
在化合物2与乙醛的混合物中加入三乙烯二胺(DABCO),将反应混合物在室温下搅拌,待反应结束后,无需柱层析纯化,浓缩获得粗产物;在缚酸剂的存在下,将粗产物在0℃下与乙酰化试剂的作用下得到乙酰化产物;准备干燥的圆底烧瓶,将频哪醇联硼酸酯溶于一定量的DMF,加入CuCl和LiCl搅拌,向反应混合物中加入KOAc,然后逐滴添加乙酰化产物溶液,将反应混合物在25℃搅拌,得到中间体化合物3;
步骤4、化合物5的合成,
将芳香醛4和中间体化合物3溶于一定量的甲苯后,在路易斯酸的作用下,室温下搅拌过夜,待反应结束后,粗品经柱层析获得中间体化合物(±)-5;
步骤5、(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成,
在获得中间体化合物(±)-5后,有两种合成路线;路线1的方法为:将中间体化合物(±)-5溶于有机溶剂,加入催化剂,然后通O2鼓泡,然后将苯硅烷稀释后缓慢加入体系,室温搅拌,反应结束后通过柱色谱法纯化粗产物,得到(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1;路线2的方法为:将中间体化合物(±)-5溶于有机溶剂后,在还原剂的作用下将双键还原,得到化合物(±)-6,继而将化合物(±)-6溶解于干燥的四氢呋喃,在一定温度下与强碱反应,拔除α位的质子,在相同温度下加入与羟基化试剂反应,待反应结束,通过柱色谱法纯化粗产物,得到(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1。
进一步地,所述步骤1~3中化合物2与乙醛的摩尔比为3:1,所述缚酸剂为三乙胺、吡啶,所述的乙酰化试剂为乙酸酐、乙酰氯;
所述步骤4中路易斯酸为Sc(OTf)3、In(OTf)3、Bu2BOTf中的一种;
步骤5中路线1所述溶剂为醇类溶剂与二氯甲烷的混合溶剂,所述催化剂为含Fe、Co、Mn金属催化剂;所述醇类溶剂为乙醇、异丙醇;所述催化剂为Fe(dpm)3、Co(dpm)3、Mn(dpm)3中的一种或多种;
步骤5中路线2所述有机溶剂为:甲醇、乙醇、甲苯、四氢呋喃;所述的还原体系为Pd/C+H2、RhCl(PPh3)3+H2、NaBH4;所述一定温度为-78℃~0℃;所述的强碱为双(三甲基硅烷基)氨基钾(KHMDS)、双(三甲基硅烷基)氨基钠(NaHMDS)、双(三甲基硅烷基)氨基锂(LiHMDS)、二异丙基氨基锂(LDA)中的一种;所述羟基化试剂为氧气、Vedejs试剂(MoOPH)、Davis试剂中的一种。
一种(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1的合成方法,该合成反应方程式如下:
进一步地,这种(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1的合成方法中,所述路线3中将芳香醛4与化合物3在甲苯中加热回流,待原料消失后加入催化量的酸,获得中间体化合物(±)-4-epi-5;
所述路线4中将芳香醛4与化合物7在金属铟或者锌的催化下发生巴比耶反应,然后加入催化量的酸,获得中间体化合物(±)-4-epi-5;在获得中间体化合物(±)-4-epi-5后,用上述中步骤5所述路线反应条件可获得(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1。
本发明的有益效果是:本发明提供具有抗烟草花叶病毒活性天然产物(±)-Nicotlactone A及其差向异构体的合成方法,该合成方法从廉价易得的丙烯酸甲酯为原料,通过Morita-Baylis-Hillman反应、乙酰化反应、硼酸酯化反应、路易斯酸催化关环反应、Mukaiyama水合反应等5步反应获得天然产物(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1,过程简单、高效、操作方便、条件温和;同时提供一种以关键中间体芳香醛4为原料,通过还原、羟基化两步反应获得天然产物(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法;同时本发明也提供了(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1的合成方法。
具体实施方式
现在结合实施例对本发明作进一步的说明。
实施例1
乙酰化化合物2-1的制备方法:室温条件下,向圆底烧瓶中依次加入丙烯酸甲酯2(12.9g,150mmol)、乙醛(10mL,50mmol)及三乙烯二胺(5%mol),然后搅拌反应7天。反应结束后依次用1M HCl、饱和NaHCO3溶液、饱和食盐水洗涤,最后无水硫酸镁干燥,减压旋干溶剂得粗产物3-羟基-2-亚甲基丁酸甲酯(6.3g);将上述粗产物溶于二氯甲烷(30mL),然后在0℃下加入吡啶(7.65g,96.8mmol),反应10min,然后加入乙酸酐(19.7g,193.6mmol),逐渐升至室温,搅拌反应过夜。反应结束后,加水(20mL)淬灭,并依次用5%HCl(3×20mL)、水(2×20mL)、饱和NaCl水溶液(3×20mL)洗涤,最后无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:10),纯化得淡黄色油状乙酰化化合物2-1(7.3g,收率85%)。1H NMR(400MHz,CDCl3)δ6.24(s,1H),5.78(s,1H),5.66(q,J=6.4Hz,1H),3.73(s,3H),2.03(s,3H),1.36(d,J=6.5Hz,3H);13C NMR(101MHz,CDCl3)δ169.8,165.8,141.1,124.8,68.2,52.0,21.2,20.2.
实施例2
化合物3的制备方法:在氩气保护下,向干燥的圆底烧瓶中依次加入CuCl(747.3mg,7.55mmol)、LiCl(320mg,7.55mmol)和DMF(10mL),室温搅拌0.5-1h;向反应混合物中加入B2Pin2(1.92g,7.55mmol)的DMF溶液(3mL),搅拌5min;向反应混合物中加入干燥的KOAc(740.9mg,7.55mmol),反应溶液变黑;最后逐滴添加中间体化合物2-1(1.0g,5.81mmol),室温搅拌4-6h。反应结束后,加水(4mL)淬灭,用乙醚(3×10mL)萃取,合并有机相并用饱和NaCl水溶液(3×10mL)洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:15)纯化得到油状中间体化合物3(1.04g,75%)。1H NMR(400MHz,CDCl3)δ6.81(q,J=7.0Hz,1H),3.68(s,3H),1.83(s,2H),1.75(d,J=7.1Hz,3H),1.21(s,12H);13CNMR(101MHz,CDCl3)δ168.6,135.9,130.1,83.4,51.7,24.8(4C),14.6.
实施例3
化合物5的制备方法:将芳香醛4(937.9mg,6.24mmol)加入到中间体3(1.0g,4.16mmol)和In(OTf)3(20%)的甲苯(10mL)溶液中,室温下搅拌过夜。反应结束后,用乙醚(3×10mL)萃取。合并有机相并用饱和NaCl水溶液洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:8)纯化得淡黄色蜡状中间体(±)-5(753mg,78%)。1H NMR(400MHz,Acetone-d6)δ6.99(s,1H),6.94(d,J=8.0Hz,1H),6.87(d,J=7.9Hz,1H),6.14(d,J=2.5Hz,1H),6.04(s,2H),5.67–5.63(m,1H),4.91(d,J=7.9Hz,1H),3.08–2.95(m,1H),1.28(d,J=6.7Hz,3H);13C NMR(101MHz,Acetone-d6)δ170.0,149.1,149.0,142.4,133.4,121.4,120.2,108.9,107.3,102.3,86.4,43.9,15.4.
实施例4
得到关键中间体化合物(±)-5后,根据合成路线1,(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的制备方法:
室温条件下,向反应管中加入化合物(±)-5(300mg,1.29mmol)和Mn(dpm)3(151mg,0.25mmol),并用O2进行气体置换。然后加入混合溶剂(EtOH/DCM=4:1,5mL),并用O2鼓泡10min。继而在O2(气球)保护下,通过注射泵缓慢加入PhSiH3(279mg,2.58mmol)的乙醇(5mL)溶液。滴加完毕后(约2h),将反应混合物在室温下继续搅拌6–8h。反应结束后,加入H2O(20mL)并用乙酸乙酯(3×10mL)萃取,合并有机相并用饱和NaCl水溶液洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:15至1:8)纯化得到(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1(180mg,56%,dr=1:1)。
化合物(±)-Nicotlactone A(1),白色固体,m.p.=139.7–140.2℃;1H NMR(400MHz,Acetone-d6)δ6.99(d,J=1.4Hz,1H),6.94(dd,J=8.0,1.5Hz,1H),6.86(d,J=7.9Hz,1H),6.03(s,2H),5.02(d,J=9.9Hz,1H),4.92(s,1H),2.17(dq,J=9.8,6.8Hz,1H),1.43(s,3H),1.01(d,J=6.8Hz,3H);13C NMR(101MHz,Acetone-d6)δ177.6,149.0(2C),132.5,122.0,108.7,107.7,102.3,85.5,74.8,50.2,21.5,7.7;HRMS(ESI)m/z:[M+Na]+Calcd for C13H14O5Na273.0733,found273.0734.
(±)-Nicotlactone A差向异构体(±)-3-epi-1,白色固体,m.p.=179.6–181.2℃;1H NMR(400MHz,Acetone-d6)δ6.98–6.83(m,3H),6.04(s,2H),4.87(d,J=10.5Hz,1H),2.41(dq,J=10.4,6.8Hz,1H),1.34(s,3H),1.00(d,J=6.9Hz,3H);13C NMR(101MHz,Acetone-d6)δ179.3,149.1(2C),132.5,121.8,108.8,107.5,102.3,83.7,75.9,50.5,18.7,9.0;HRMS(ESI)m/z:[M+Na]+Calcd for C13H14O5Na 273.0733,found273.0733.
实施例5
得到关键中间体化合物(±)-5后,根据(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1合成路线2,化合物(±)-6的制备方法:
中间体化合物(±)-5(100mg,0.43mmol)溶解于EtOH(3mL),加入10%Pd/C(10mg),然后在H2(1个大气压)条件下反应6h。反应结束后,过滤除去Pd/C,EtOH洗涤,减压浓缩除去溶剂,硅胶柱层析(乙酸乙酯/石油醚=1:5)纯化得到无色油状化合物(±)-6(64mg,64%,dr=6:1)。主异构体:1H NMR(400MHz,CDCl3)δ6.89–6.70(m,3H),5.97(d,J=2.6Hz,2H),4.72(dd,J=9.9,2.6Hz,1H),2.40–2.25(m,1H),1.97(ddd,J=11.8,7.7,4.6Hz,1H),1.29(dd,J=7.1,2.5Hz,3H),1.11(dd,J=6.6,2.6Hz,3H);13C NMR(101MHz,CDCl3)δ178.5,148.2,148.2,131.3,120.5,108.3,106.7,101.4,86.4,47.9,43.5,14.4,13.1;HRMS(ESI)m/z:[M+Na]+Calcdfor C13H14O4Na257.0783,found257.0784.
实施例6
得到中间体化合物(±)-6后,根据合成路线2,(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法:
将化合物(±)-6(50mg,0.21mmol)溶解于无水THF(2mL),然后在–78℃条件下,加入1.0M KHMDS(0.42mmol),在同样温度下搅拌30min后,加入(1R)-(-)-10-樟脑磺哑嗪(108.9mg,0.42mmol)的THF溶液(1mL),并搅拌1h。反应结束后,加入饱和NH4Cl水溶液(1mL)淬灭。乙酸乙酯(3×10mL)萃取,合并有机相并依次用水(2mL),饱和NaCl水溶液(2mL)洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:10)纯化得到(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1(38mg,74%,dr=1:1)
实施例7
根据(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1的合成路线3中化合物(±)-4-epi-5的制备方法:将芳香醛4(585.2mg,3.89mmol)加到取代烯丙基硼酸酯3(1.12g,4.67mmol)的甲苯溶液中,在110℃条件下回流2d。反应完成后(TLC监测),减压浓缩的粗产物;将上述粗品溶解于二氯甲烷中,加入p-TSA(20%),并在40℃下回流反应5h,最后加入饱和NaHCO3水溶液(2mL)淬灭,用乙醚(3×10mL)萃取,合并有机相并用饱和盐水洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:10)纯化得到淡黄色蜡状化合物(±)-4-epi-5(668.5mg,74%)。1H NMR(400MHz,CDCl3)δ6.78(d,J=7.9Hz,1H),6.63(d,J=8.1Hz,2H),6.32(d,J=2.9Hz,1H),5.97(s,2H),5.57(d,J=2.7Hz,1H),5.52(d,J=8.1Hz,1H),3.39(ddt,J=8.0,7.0,2.9Hz,1H),0.84(d,J=7.0Hz,3H);13C NMR(101MHz,CDCl3)δ170.6,148.1,147.8,140.1,130.3,121.9,119.9,108.3,106.6,101.4,82.3,39.1,15.3.
实施例8
根据(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1合成路线4中化合物(±)-4-epi-5的制备方法:
向圆底烧瓶中依次加入芳香醛4(272.3mg,2.66mmol)、(Z)-2-(溴甲基)丁-2-烯酸甲酯(7,342.9mg,1.77mmol)、THF(9mL)、饱和NH4Cl溶液(3mL)和铟粉(264.2mg,2.3mmol),室温下搅拌12h。反应结束后,分离有机层,水相用乙酸乙酯萃取。合并有机相,饱和NH4Cl水溶液洗涤,无水硫酸镁干燥,减压浓缩。硅胶柱层析纯化得到相应的中间体醇(397.6mg,85%)。在室温下,将得到的中间体醇(397.6mg,1.5mmol)溶解于无水二氯甲烷(8mL)中,然后加入p-TSA(57mg,0.3mmol),搅拌反应12h后,向反应混合物加入硅胶,并减压浓缩。硅胶柱层析(乙酸乙酯/石油醚=1:10)纯化得化合物(±)-4-epi-5(261.2mg,75%)。
实施例9
(±)-Nicotlactone A的差向异构体(±)-4-epi-1和(±)-3,4-epi-1合成:利用(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法中实施例4或实施例5的方法,只需将中间体化合物(±)-5替换为化合物(±)-4-epi-5,即可获得(±)-Nicotlactone A差向异构体(±)-4-epi-1和(±)-3,4-epi-1,产率为53%。
化合物(±)-4-epi-1:主产物,白色粉末状固体;1H NMR(400MHz,Acetone-d6)δ6.88(d,J=8.0Hz,1H),6.84–6.75(m,2H),6.02(s,2H),5.84(d,J=5.6Hz,1H),5.07(s,1H),2.72–2.54(m,1H),1.34(s,3H),0.59(d,J=7.5Hz,3H);13C NMR(101MHz,Acetone-d6)δ177.6,148.8,148.1,131.8,119.6,108.9,106.9,102.2,81.6,77.3,47.1,20.1,10.7;HRMS(ESI)m/z:[M+H]+Calcd for C13H15O5 +251.0914,found251.0915.
化合物(±)-3,4-epi-1:白色粉末固体;1H NMR(400MHz,Acetone-d6)δ6.89(s,1H),6.88–6.78(m,2H),6.01(s,2H),5.60(d,J=6.5Hz,1H),4.80(s,1H),2.68(p,J=7.3Hz,1H),1.54(s,3H),0.67(d,J=7.4Hz,3H);13C NMR(101MHz,Acetone)δ179.0,148.7,148.2,132.0,120.6,108.7,107.5,102.1,81.6,75.3,46.1,24.3,9.7;HRMS(ESI)m/z:[M+H]+Calcd for C13H15O5 +251.0914,found251.0915.
综上所述,本发明提供具有抗烟草花叶病毒活性天然产物(±)-Nicotlactone A及其差向异构体的合成方法,该合成方法过程简单、高效、操作方便、条件温和。
以上述依据本发明的理想实施例为启示,通过上述的说明内容,相关工作人员完全可以在不偏离本项发明技术思想的范围内,进行多样的变更以及修改。本项发明的技术性范围并不局限于说明书上的内容,必须要根据权利要求范围来确定其技术性范围。
Claims (5)
3.根据权利要求1所述的(±)-Nicotlactone A(1)及其差向异构体(±)-3-epi-1的合成方法,其特征在于:该合成方法具体包括如下步骤:
步骤1~3、化合物3的合成,
在化合物2与乙醛的混合物中加入三乙烯二胺,将反应混合物在室温下搅拌,待反应结束后,无需柱层析纯化,浓缩获得粗产物;在缚酸剂的存在下,将粗产物在0℃下与乙酰化试剂的作用下得到乙酰化产物;准备干燥的圆底烧瓶,将频哪醇联硼酸酯溶于一定量的DMF,加入CuCl和LiCl搅拌,向反应混合物中加入KOAc,然后逐滴添加乙酰化产物溶液,将反应混合物在25℃搅拌,得到中间体化合物3;
步骤4、化合物5的合成,
将芳香醛4和中间体化合物3溶于一定量的甲苯后,在路易斯酸的作用下,室温下搅拌过夜,待反应结束后,粗品经柱层析获得中间体化合物(±)-5;
步骤5、(±)-NicotlactoneA(1)及其差向异构体(±)-3-epi-1的合成,
在获得中间体化合物(±)-5后,有两种合成路线;路线1的方法为:将中间体化合物(±)-5溶于有机溶剂,加入催化剂,然后通O2鼓泡,然后将苯硅烷稀释后缓慢加入体系,室温搅拌,反应结束后通过柱色谱法纯化粗产物,得到(±)-NicotlactoneA(1)及其差向异构体(±)-3-epi-1;路线2的方法为:将中间体化合物(±)-5溶于有机溶剂后,在还原剂的作用下将双键还原,得到化合物(±)-6,继而将化合物(±)-6溶解于干燥的四氢呋喃,在一定温度下与强碱反应,拔除α位的质子,在相同温度下加入与羟基化试剂反应,待反应结束,通过柱色谱法纯化粗产物,得到(±)-NicotlactoneA(1)及其差向异构体(±)-3-epi-1。
4.根据权利要求3所述的(±)-NicotlactoneA(1)及其差向异构体(±)-3-epi-1的合成方法,其特征在于:所述步骤1~3中化合物2与乙醛的摩尔比为3:1,所述缚酸剂为三乙胺、吡啶,所述的乙酰化试剂为乙酸酐、乙酰氯;
所述步骤4中路易斯酸为Sc(OTf)3、In(OTf)3、Bu2BOTf中的一种;
步骤5中路线1所述溶剂为醇类溶剂与二氯甲烷的混合溶剂,所述催化剂为含Fe、Co、Mn金属催化剂;所述醇类溶剂为乙醇、异丙醇;所述催化剂为Fe(dpm)3、Co(dpm)3、Mn(dpm)3中的一种或多种;
步骤5中路线2所述有机溶剂为:甲醇、乙醇、甲苯、四氢呋喃;所述的还原体系为Pd/C+H2、RhCl(PPh3)3+H2、NaBH4;所述一定温度为-78℃~0℃;所述的强碱为双(三甲基硅烷基)氨基钾、双(三甲基硅烷基)氨基钠、双(三甲基硅烷基)氨基锂、二异丙基氨基锂中的一种;所述羟基化试剂为氧气、Vedejs试剂、Davis试剂中的一种。
5.根据权利要求2所述的(±)-NicotlactoneA的差向异构体(±)-4-epi-1和(±)-3,4-epi-1的合成方法,其特征在于:所述路线3中将芳香醛4与化合物3在甲苯中加热回流,待原料消失后加入催化量的酸,获得中间体化合物(±)-4-epi-5;
所述路线4中将芳香醛4与化合物7在金属铟或者锌的催化下发生巴比耶反应,然后加入催化量的酸,获得中间体化合物(±)-4-epi-5;在获得中间体化合物(±)-4-epi-5后,用权利要求3中步骤5所述路线反应条件可获得(±)-NicotlactoneA的差向异构体(±)-4-epi-1和(±)-3,4-epi-1。
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