CN116970030A - 一种环酯肽类反应中间体及天然产物的合成方法 - Google Patents
一种环酯肽类反应中间体及天然产物的合成方法 Download PDFInfo
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- -1 Cyclic ester Chemical class 0.000 title claims abstract description 55
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- 238000001308 synthesis method Methods 0.000 title description 7
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- 150000001875 compounds Chemical class 0.000 claims description 23
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 11
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
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- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及合成化学领域,尤其涉及一种环酯肽类反应中间体及天然产物的合成方法。本发明首次化学合成了活性天然环酯肽colletopeptide A和colletotrichamide A及其反应中间体,克服了目前缺乏高效合成天然环酯肽colletopeptide A和colletotrichamide A的方法的问题,而且,该全合成方法具有工艺简单、成本低和产率高的特点,具有很强的医药工业应用前景。
Description
技术领域
本发明涉及合成化学领域,尤其涉及一种环酯肽类反应中间体及天然产物的合成方法。
背景技术
具有优秀抗炎活性的环酯肽类天然产物colletopeptide A是由谭宁华课题组(Tan,N.H.;et al.,J.Nat.Prod.2019,82,1434)在2019年从茜草科植物的内生真菌中分离得到。Colletotrichamides A是在同年,由Shim研究团队(Shim,S.H.;et al.,J.Org.Chem.2019,84,10999)从盐生植物Suaeda japonica的共生真菌Colletotrichumgloeosporioides JS419的培养物中分离得到的新型化合物。
Colletopeptide A和colletotrichamide A在结构上有很大的类似性,两个化合物共有一个相同的环酯肽母核,唯一的区别便是colletotrichamide A在colletopeptideA的侧链羟基上接了一个D-甘露糖单元。自2019年分离以来,围绕该类分子的合成以及活性研究便从未间断。Colletopeptide A能够抑制脂多糖诱导的硝酸RAW264.7巨噬细胞中氧化物的产生,IC50值为8.3μM,此外,该分子还具有抑制炎症因子IL-6和TNF-α,并降低NF-κB相关蛋白IκBα和p65的磷酸化的功能。
鉴于colletopeptide A和colletotrichamide A代表了一种新型的抗炎活性化合物,针对colletopeptide A和colletotrichamide A展开深入的合成及构效关系研究对于新的抗炎药的开发具有重要意义。然而,目前还未见有报道此环酯肽类天然产物的化学合成方法。
因此,现有技术仍有待于改进和发展。
发明内容
鉴于上述现有技术的不足,本发明提供了一种环酯肽类反应中间体及天然产物的合成方法,首次化学合成了活性天然环酯肽colletopeptide A和colletotrichamide A及其反应中间体,旨在解决现有技术缺乏高效合成天然环酯肽colletopeptide A和colletotrichamide A的方法的问题。
为了完成环酯肽类天然产物colletopeptide A和colletotrichamide A的全合成,发明人对其逆合成进行了分析,并对反应中间体的合成路线进行了深入研究,在付出了大量创造性劳动后,从而首次实现了环酯肽类天然产物的全化学合成。
具体地,本发明的技术方案如下:
本发明提供一种环酯肽类反应中间体,所述反应中间体的结构式如下:
所述反应中间体用于制备天然环酯肽colletopeptide A和colletotrichamideA。
本发明提供一种所述的环酯肽类反应中间体的合成方法,包括:
在氟甲磺酸三甲基硅酯和三乙胺的条件下,化合物25脱除Boc基团,再在催化条件下发生大环内酰胺化反应,生成化合物4;
在钯碳的条件下,所述化合物4脱除苄基保护,得到所述反应中间体;
其中,所述化合物25和所述化合物4的结构式如下所示:
在TMSOTf和三乙胺存在的条件下,所述化合物25选择性脱除氮原子上的叔丁氧羰Boc保护基团,再发生大环内酰胺化反应,生成化合物4。
可选地,所述催化采用多肽缩合催化剂和肽偶联剂,所述多肽缩合催化剂为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU,所述肽偶联剂为N-羟基-7-氮杂苯并三氮唑HOAt。
可选地,所述化合物25的合成路线如下所示:
在以上合成路线中,单烯化合物5与已知的Boc保护的N-甲基异亮氨酸片段7在2,4,6-三氯苯甲酰氯TCBC的催化和碱三乙胺的存在下发生酯化反应,其产物在TMSOTf(三氟甲磺酸三甲基硅酯)的条件下选择性的脱除氮原子上的Boc保护基团;随后与Boc保护的苯丙氨酸片段6在多肽缩合催化剂和肽偶联剂的介导下发生酰胺化反应,生成的化合物20在钯碳催化下进行加氢反应生成化合物21;在CSA(樟脑磺酸)酸性条件下,化合物21脱除羟基上的TBS保护基团,得到裸露的羟基紧接着被Dess-Martin试剂氧化为醛化合物22,然后在手性催化剂Ipc2BOMe的催化下与反式-2-丁烯发生不对称丁烯基化反应,得到手性醇化合物23,化合物23中心生成的羟基被保护为TBS硅醚化合物24,化合物24中的末端双键发生臭氧断键反应生成醛中间体,该中间体进一步在TEMPO和PhI(OAc)2存在下被氧化为羧酸化合物25。
可选地,所述化合物5的合成方法,包括:
在Grubbs II催化剂的条件下,化合物14和化合物11进行交叉烯烃复分解反应,生成化合物5;
所述交叉烯烃复分解反应如下所示:
所述化合物14的合成从已知的丙二醇化合物12出发,进行选择性单保护其中一个羟基为TBS硅醚,另一个裸露羟基被Dess-Martin试剂氧化为醛,制得化合物13。化合物13在手性催化剂Ipc2BOMe的催化下发生丁烯基化反应,得到手性醇化合物14。具体地,在叔丁基二甲基氯硅烷和咪唑的条件下,对1,3-丙二醇的羟基进行选择性的叔丁基二甲基硅基TBS单保护;加入Dess-Martin试剂氧化未被保护的羟基为醛基,生成的化合物13在手性催化剂Ipc2BOMe(甲氧基双((1R,2S,3R,5R)-2,6,6-三甲基双环[3.1.1]庚烷-3-基)硼烷)的催化下与顺式-2-丁烯发生反应,生成所述化合物14。其合成路线可以表示为:
可选地,所述化合物11的合成方法,包括:
在碘化亚铜的催化下,化合物9在格氏试剂烯丙基溴化镁的亲核进攻下开环反应,生成化合物10;
所述化合物10的羟基被苄基保护,得到化合物11;
所述化合物9、10和11的结构式如下所示:
发明人利用经典的逆合成分析对环酯肽类天然产物colletopeptide A和colletotrichamide A的合成进行了分析,其逆合成分析如下:
将colletotrichamide A逆推到糖苷化合物3和天然产物colletopeptide A及分子中两个羟基分别被TBS和Bn保护的化合物4,化合物4脱去苄基保护后得到反应中间体。所述化合物4可以由Boc保护的苯丙氨酸片段6、Boc保护的N-甲基异亮氨酸片段7和手性单烯片段5经过一系列的脱保护、酯化和大环内酰胺化制得。
在以上所述的环酯肽类反应中间体的合成方法中,经过了叔丁基二甲基硅基TBS单保护和氧化反应、不对称丁烯基化反应、交叉烯烃复分解反应、酯化反应、酰胺化反应、加氢反应、TBS脱保护和氧化反应、不对称丁烯基化反应、TBS保护、氧化成酸反应、叔丁氧羰基团Boc脱保护和大环内酰胺化反应和苄基Bn脱保护等一系列反应,最终得到了所述反应中间体。
本发明另提供一种环酯肽类天然产物的合成方法,经所述的反应中间体反应得到环酯肽类天然产物中的colletopeptide A和colletotrichamide A;
所述环酯肽类天然产物的结构式如下所示:
可选地,所述的环酯肽类天然产物的合成方法,包括步骤:
经所述的反应中间体在TBAF的条件下脱除TBS保护基,得到环酯肽colletopeptide A。
可选地,所述的环酯肽类天然产物的合成方法,包括步骤:
经所述的反应中间体与化合物3进行糖苷化反应生成化合物27;
将所述化合物27的TBS保护基进行脱保护,在钯碳加氢的条件下脱除糖苷上的芳基保护基团,得到环酯肽colletotrichamide A;
所述化合物3和化合物27的结构式如下:
可选地,所述化合物3的合成方法,包括步骤:
D-甘露糖、乙酸酐和4-二甲氨基吡啶反应,将羟基保护为乙酸酯,再和对甲苯硫酚在三氟化硼乙醚的介导下反应,生成化合物15;
所述化合物15与甲醇钠进行皂化反应,生成化合物16;
所述化合物16和苯甲醛二甲缩醛发生反应,生成化合物17;
在氢化钠和N,N-二甲基甲酰胺的条件下,所述化合物17与苄化溴反应,生成化合物18;
在间氯过氧苯甲酸的条件下,所述化合物18发生氧化,得到化合物3;
所述化合物3的合成路线如下所示:
由于colletotrichamide A中糖苷键的不稳定性,发明人选择通过亲核取代构建该结构。糖苷化合物3由D-甘露糖(D-mannose)经过一系列的化学转化制备得。具体地,先将D-甘露糖中的四个羟基保护为乙酰基,接下来在三氟化硼乙醚的介导下,制得硫醚化合物15;将化合物15的四个乙酰基在甲醇钠催化下脱除,生成裸露四醇化合物16。然后,化合物16其中两个裸露的羟基保护为苯叉,得到化合物17。继续把化合物17中剩余两个裸露的羟基保护为苄醚得到化合物18。最后,化合物18在间氯过氧苯甲酸的氧化下,将硫醚官能团转化为亚砜,得到糖苷片段化合物3。
本发明提供了一种环酯肽类反应中间体及天然产物的合成方法,首次合成了活性天然环酯肽colletopeptide A和colletotrichamide A及其反应中间体,解决了现有技术缺乏高效合成天然环酯肽colletopeptide A和colletotrichamide A的方法的问题,同时本发明的合成方法具有工艺简单、成本低和产率高的特点,具有很强的医药工业应用前景。
附图说明
图1为本发明实施例2和3中制备得到的环酯肽类天然产物colletopeptide A和colletotrichamide A的结构式。
具体实施方式
本发明提供一种环酯肽类反应中间体及天然产物的合成方法,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明的保护范围。
下面以具体的实施例对本发明的方案作进一步的说明。
实施例1
反应中间体的制备
(1)
将D-甘露糖(5.0g,27.8mmol,1.0equiv)和乙酸酐(19.6mL,208.5mmol,7.5equiv)溶于吡啶(80mL,0.35M)中,随后加入4-二甲氨基吡啶(340mg,2.78mmol,0.1equiv)。反应液在室温下继续搅拌13小时,随后经真空泵减压浓缩除去吡啶后,反应液用乙酸乙酯(250mL)稀释,并依次用1M的盐酸溶液(50mL)和饱和氯化钠溶液(50mL)洗涤,通过无水硫酸钠干燥后,干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物直接用于下一步。
将上一步粗产物和对甲苯硫酚(5.1mL,41.7mmol,1.5equiv.)溶于二氯甲烷(200mL,0.14M)中,并将反应体系冷却至0℃,随后加入三氟化硼.乙醚(10.3mL,83.4mmol,3.0equiv)。将反应体系缓慢恢复至室温,并在室温下继续搅拌9h后,在0℃下加入饱和碳酸氢钠溶液(50mL)淬灭反应,反应液用乙酸乙酯(100mL x 3)萃取,合并的有机相依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤,通过无水硫酸钠干燥后,干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/1)得到无色油状物15(7.6g,16.7mmol,60%)。
TLC:Rf=0.50(薄层硅胶板,乙酸乙酯/正己烷=1/2)。紫外荧光&磷钼酸显色,1HNMR(500MHz,CDCl3)7.31(d,J=8.2Hz,2H),7.05(d,J=7.9Hz,2H),5.45–5.39(m,1H),5.35(d,J=1.6Hz,1H),5.29–5.23(m,2H),4.49(dp,J=8.1,2.4Hz,1H),4.23(dd,J=12.2,5.9Hz,1H),4.05–4.00(m,1H),2.26(s,3H),2.04–1.78(m,12H)。13C NMR(126MHz,CDCl3)δ170.9,169.7,169.6,169.6,138.3,132.6,129.9,128.7,85.9,70.8,69.4,69.3,66.3,62.4,21.0,20.7,20.6,20.6,20.5。
(2)
将化合物15(3.0g,6.6mmol,1.0equiv)溶于甲醇(50mL,0.13M)中,随后加入甲醇钠(357mg,6.6mmol,1.0equiv)。反应液在室温下继续搅拌9小时,经TLC监测确认化合物15转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(20mL)淬灭反应并用乙酸乙酯(3×30mL)萃取,将合并的有机相用饱和食盐水溶液(30mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(甲醇/二氯甲烷=1/10)即可以91%的产率得到白色固体16(1.7g,6.0mmol)。
TLC:Rf=0.40(薄层硅胶板,甲醇/二氯甲烷=1/10)。紫外荧光&磷钼酸显色,1HNMR(400MHz,MeOD)δ7.41(d,J=8.2Hz,2H),7.13(d,J=7.9Hz,2H),5.35(d,J=1.6Hz,1H),4.10–4.04(m,1H),4.03(dd,J=5.6,2.9Hz,1H),3.86–3.73(m,2H),3.75–3.63(m,2H),2.31(s,3H)。13C NMR(101MHz,MeOD)δ138.9,133.5,132.1,130.7,90.8,75.5,73.7,73.1,68.7,62.6,21.1。
(3)
将化合物16(1.0g,3.5mmol,1.0equiv.)溶于乙腈(50mL,0.07M)和苯甲醛二甲缩醛(0.55mL,3.67mmol,1.05equiv.)的混合溶液中,并冷却至0℃,随后加入樟脑磺酸(203mg,0.875mmol,0.25equiv.)。反应液在60℃下继续搅拌3小时,经TLC监测确认原料16转化完全后,向反应液中滴加三乙胺(0.3mL),随后经真空泵减压浓缩获得粗产物17直接用于下一步。
将氢化钠(308mg,7.7mmol,60%dispersion in mineral oil,2.2equiv.)溶于N,N-二甲基甲酰胺(10mL)中,搅拌形成悬浊液,在0℃下缓慢加入粗产物的N,N-二甲基甲酰胺(50mL,0.07M)溶液。10min后,将苄化溴(0.9mL,7.7mmol,2.2equiv.)缓慢滴加到反应体系中。将反应体系缓慢恢复至室温,并在室温下继续搅拌6h后,在0℃下加入饱和氯化铵溶液(10mL)淬灭反应。通过旋转蒸发仪减压除去低沸点溶剂后,反应液用乙酸乙酯(50mL x 3)萃取,合并的有机相依次用水(5mL x 3)和饱和氯化钠溶液(5mL x3)洗涤,通过无水硫酸钠干燥后,干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)得到白色不定型固体18(1.41g,2.55mmol,73%)。
TLC:Rf=0.50(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色,1HNMR(400MHz,CDCl3)δ7.65–7.51(m,2H),7.47–7.29(m,15H),7.19–7.05(m,2H),5.69(s,1H),5.49(d,J=1.5Hz,1H),4.87(dd,J=12.2,2.0Hz,1H),4.76(d,J=1.9Hz,2H),4.70(dd,J=12.3,2.0Hz,1H),4.36(m,J=6.3,4.1Hz,2H),4.27(dd,J=10.1,3.6Hz,1H),4.08(dt,J=2.9,1.5Hz,1H),4.03(dt,J=9.5,3.0Hz,1H),3.93(td,J=10.1,8.8,3.1Hz,1H),2.37(s,2H)。13C NMR(101MHz,CDCl3)δ138.5,138.1,137.9,137.7,132.4,130.0,129.9,129.0,128.5,128.5,128.3,128.2,127.9,127.7,127.7,126.2,101.6,87.5,79.2,78.1,76.3,73.2,73.1,68.6,65.5,21.2.HRMS(ESI,m/z)for C34H35O5S+[M+H]+:Calcd.555.2205;Found 555.2230。
(4)
将化合物18(800mg,1.4mmol,1.0equiv.)溶解于二氯甲烷(30mL,0.05M)中,在-78℃下缓慢滴加间氯过氧苯甲酸(266mg,1.54mmol,1.1equiv.)的二氯甲烷(5mL)溶液。将反应体系缓慢升温至-35℃,并在该温度下继续搅拌1h后,依次加入饱和碳酸氢钠溶液(10mL)和硫代硫酸钠溶液(10mL)淬灭反应。反应液用乙酸乙酯(100mL x 3)萃取,合并的有机相依次用水(10mL)和饱和氯化钠溶液(10mL)洗涤,通过无水硫酸钠干燥后,干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/3)得到白色固体化合物3(694mg,1.22mmol,87%)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,1HNMR(400MHz,CDCl3)δ7.55–7.46(m,2H),7.43–7.27(m,12H),7.27–7.19(m,5H),5.61(s,1H),4.81(d,J=12.1Hz,1H),4.66(d,J=12.1Hz,1H),4.58(s,2H),4.47(d,J=1.2Hz,1H),4.39(dd,J=3.0,1.4Hz,1H),4.37–4.25(m,2H),4.19(dd,J=10.2,4.8Hz,1H),4.08(ddd,J=13.2,6.9,3.1Hz,1H),3.73(t,J=10.1Hz,1H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ142.2,138.3,138.2,137.4,137.3,130.2,129.0,128.4,128.3,128.2,127.9,127.8,127.6,126.1,124.4,101.6,97.5,78.1,76.3,73.4,73.2,72.8,70.1,68.2,21.6.HRMS(ESI,m/z)for C34H35O6S+[M+H]+:Calcd.571.2154;Found 571.2140。
(5)
将化合物12(2.0g,26mmol,1.0equiv.)溶解在无水的二氯甲烷(200mL,0.125M)中并冷却至0℃,然后依次加入叔丁基二甲基氯硅烷(4.31g,28.6mmol,1.1equiv.)和咪唑(2.65g,28.6mmol,1.5equiv.)。反应体系升至室温并持续搅拌5小时,经TLC监测确认化合物12转化完全后,在0℃下缓慢加入饱和氯化铵溶液,再加入二氯甲烷(3×150mL)萃取,合并得到的有机相用饱和食盐水溶液(50mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/4)即可以73%的产率得到无色油状叔丁基二甲基硅基TBS单保护化合物(3.76g,19.76mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,1HNMR(400MHz,CDCl3)δ3.78(dt,J=15.3,5.7Hz,4H),2.76(s,1H),1.75(p,J=5.6Hz,2H),0.87(s,9H),0.05(s,6H)。13C NMR(101MHz,CDCl3)δ62.8,62.3,34.4,26.0,18.3,-5.4.HRMS(ESI,m/z)for C9H23O2Si+[M+H]+:Calcd.191.1467;Found:191.1462。
将叔丁基二甲基硅基TBS单保护化合物(1.0g,5.3mmol,1.0equiv.)溶解在无水的二氯甲烷(20mL,0.26M)中并冷却至0℃,然后加入戴斯马丁试剂(2.7g,6.36mmol,1.2equiv.)。反应体系升至室温并持续搅拌4小时,经TLC监测确认转化完全后,在0℃下缓慢加入饱和亚硫酸钠溶液(20mL)将反应淬灭。再加入乙酸乙酯(3×50mL)萃取,合并得到的有机相用饱和食盐水溶液(50mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/3)即可以91%的产率得到无色油状化合物13(866mg,4.61mmol)。
TLC:Rf=0.50(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,1HNMR(400MHz,CDCl3)δ9.77(t,J=2.1Hz,1H),3.96(t,J=6.0Hz,2H),2.57(td,J=6.0,2.1Hz,2H),0.86(s,9H),0.04(s,6H)。13C NMR(101MHz,CDCl3)δ202.06,57.50,46.67,25.91,18.31,-5.35.HRMS(ESI,m/z)for C9H21O2Si+[M+H]+:Calcd.189.1311;Found:189.1312。
(6)
称取叔丁醇钾(2.98g,26.58mmol,5.0equiv.)于圆底烧瓶中在130℃下抽真空活化9小时,然后加入四氢呋喃(150mL,0.18M)将其溶解,冷却到-78℃加入顺式-2-丁烯(2.09g,37.24mmol,7.0equiv.)随后逐滴滴加正丁基锂(16.61mL,26.58mmol,1.6M溶解于正己烷,5.0equiv.)伴随着反应液变成橘黄色。然后升温至-45℃反应30分钟随后再降温到-78℃。紧接着在手套箱中称取(+)-B-甲氧基二异松莰基硼烷(10.1g,31.92mmol,6.0equiv.)并溶解在四氢呋喃(50mL)加入,逐滴滴加同时反应液变成亮黑色。30分钟后逐滴滴加三氟化硼.乙醚(5.25mL,42.56mmol,8.0equiv.),紧接着将化合物13(1g,5.32mmol,1.0equiv.)溶解在四氢呋喃(30mL)中逐滴加入。然后在-78℃反应3个小时,经TLC监测确认原料转化完全后,用甲醇(50mL)将反应淬灭再恢复室温,经真空泵减压浓缩获得粗产物。再将粗产物溶解在四氢呋喃(150mL)/水(100mL)的混合溶剂中,在室温向其中加入四水合过硼酸钠(4.1g,26.58mmol,5.0equiv.),反应体系在室温持续搅拌3小时。用乙酸乙酯(3×100mL)萃取,将合并的有机相用饱和食盐水溶液(30mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)即可以71%的产率和dr值大于20:1的立体选择性得到无色油状化合物14(5.52g,22.59mmol)。
TLC:Rf=0.3(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色, (c 1.70,CHCl3).1H NMR(400MHz,CDCl3)δ5.81(ddd,J=17.7,9.8,7.7Hz,1H),5.06(qt,J=2.1,1.2Hz,1H),5.03(qd,J=2.0,1.0Hz,1H),3.87(dt,J=9.8,4.8Hz,1H),3.82–3.74(m,1H),3.70–3.57(m,1H),2.32–2.08(m,1H),1.67–1.46(m,2H),1.03(t,J=6.8Hz,3H),0.88(s,9H),0.05(d,J=0.8Hz,6H)。13C NMR(101MHz,CDCl3)δ140.8,115.2,75.1,62.9,44.1,35.7,26.0,18.3,15.9,-5.4.HRMS(ESI,m/z)for C13H29O2Si+[M+H]+:Calcd.245.1937;Found:245.1931。
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将化合物14(500mg,2.05mmol,1.0equiv.)和化合物11(584mg,3.07mmol,1.5equiv.)溶解在二氯甲烷(40mL,0.051M)中,向其中加入GrubbsⅡ催化剂(348mg,0.41mmol,0.20equiv.)。反应体系升温至50℃并搅拌回流9小时,经TLC监测确认原料14转化完全后,反应液直接经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/3)即可以81%的产率得到无色油状化合物5(675mg,1.66mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,(c 1.20,CHCl3).1H NMR(500MHz,CDCl3)δ7.37–7.30(m,4H),7.29–7.23(m,1H),5.50–5.40(m,1H),5.37–5.29(m,1H),4.57(d,J=11.8Hz,1H),4.44(d,J=11.7Hz,1H),3.88(dt,J=9.9,4.9Hz,1H),3.78(ddd,J=10.0,8.7,3.9Hz,1H),3.59(ddd,J=8.9,6.4,2.1Hz,1H),3.55–3.45(m,1H),3.33–3.21(m,1H),2.24–2.15(m,1H),2.15–2.03(m,2H),1.75–1.63(m,1H),1.63–1.54(m,1H),1.54–1.44(m,1H),1.19(d,J=6.1Hz,3H),1.02(d,J=6.8Hz,3H),0.90(s,9H),0.08(s,6H).13C NMR(126MHz,CDCl3)δ139.3,133.0,130.7,128.4,127.8,127.5,75.7,74.5,70.5,63.0,43.2,36.7,35.9,28.9,26.0,19.7,18.3,16.2,-5.4,-5.4.HRMS(ESI,m/z)for C24H43O3Si+[M+H]+:Calcd.407.2981;Found:407.2976。
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将化合物5(300mg,0.74mmol,1.0equiv.)和7(272mg,1.11mmol,1.5equiv.)溶解在无水的甲苯(10mL,0.074M)中并冷却至0℃,然后依次加入2,4,6-三氯苯甲酰氯(0.35mL,2.22mmol,3.0equiv.)和三乙胺(0.41mL,2.96mmol,4.0equiv.)。反应体系升至室温并续搅拌0.5小时,随后将4-二甲氨基吡啶(542mg,4.44mmol,6.0equiv)溶解在甲苯(3mL)中逐滴加入,随后反应体系升至室温,并继续搅拌9小时,经TLC监测确认转化完全后,在0℃下缓慢加入饱和碳酸氢钠水溶液(5mL)淬灭反应,并用乙酸乙酯(3×20mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)即可以76%的产率得到无色油状化合物19(356mg,0.56mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色,(c 0.75,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ7.45–7.29(m,4H),7.26(dt,J=7.5,2.8Hz,1H),5.55–5.37(m,1H),5.32(dd,J=15.4,7.5Hz,1H),4.96–4.83(m,1H),4.56(d,J=11.8Hz,1H),4.51(d,J=8.0Hz,0.5H),4.43(d,J=11.8Hz,1H),4.27(d,J=10.7Hz,0.5H),3.68–3.54(m,1H),3.57–3.45(m,2H),2.80(d,J=16.3Hz,3H),2.38(ddp,J=22.6,14.1,6.9Hz,1H),2.23–2.03(m,2H),2.01–1.92(m,1H),1.82–1.73(m,1H),1.67(dddd,J=16.5,9.3,4.4,1.7Hz,2H),1.45(s,11H),1.19(dd,J=6.4,2.2Hz,3H),1.07(ddd,J=13.8,8.9,7.1Hz,1H),0.99–0.94(m,3H),0.93–0.90(m,3H),0.89–0.85(m,13H),0.02(s,6H)。13C NMR(126MHz,CDCl3)(Mixture of conformers)δ171.1,170.6,156.1,155.6,139.2,133.7,131.5,131.2,128.4,127.7,127.6,127.5,80.1,79.9,75.1,74.4,70.4,63.5,62.3,59.8,59.5,59.5,40.5,40.3,39.7,36.6,34.7,34.6,33.3,33.2,30.2,29.9,28.8,28.5,26.0,25.9,24.9,19.7,19.5,18.3,18.3,16.2,16.0,10.8,10.3,-5.2,-5.3.HRMS(ESI,m/z)for C36H64NO6Si+[M+H]+:Calcd.634.4503;Found:634.4531。/>
(9)
将化合物19(300mg,0.474mmol,1.0equiv.)溶解在无水的二氯甲烷(10.0mL,0.047M)中并冷却至0℃,然后依次加入三乙胺(0.46mL,3.32mmol,7equiv.)和三氟甲磺酸三甲基硅酯(0.53mL,2.37mmol,5equiv.)。反应体系升至室温并持续搅拌2小时,经TLC监测确认化合物19转化完全后,在0℃下缓慢加入饱和碳酸氢钠水溶液(10mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,粗产物不需经过纯化直接用于下一步。
将上一步粗产物和化合物6(189mg,0.711mmol,1.5equiv.)溶解在无水的二氯甲烷(10mL,0.047M)中并冷却至0℃,然后依次加入N,N-二异丙基乙胺(0.25mL,1.42mmol,3.0equiv.)、N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(361mg,0.95mmol,2.0equiv.)和N-羟基-7-氮杂苯并三氮唑(97mg,0.711mmol,1.5equiv.)。反应体系升至室温并持续搅拌9小时,经TLC监测确认原料转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(5mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)即两步反应以59%的产率得到无色油状化合物20(226mg,0.29mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色,(c 3.0,CHCl3).1H NMR(400MHz,CDCl3)(Mixture of conformers)δ7.30(dd,J=5.6,2.6Hz,4H),7.26–7.12(m,6H),5.38(dt,J=16.3,6.6Hz,1H),5.28(dd,J=13.7,8.1Hz,1H),5.17(dd,J=9.3,3.4Hz,0.5H),5.01(dd,J=9.6,3.5Hz,0.5H),4.89(qd,J=8.8,7.4,4.6Hz,1H),4.77(d,J=10.7Hz,1H),4.60–4.50(m,1H),4.47(d,J=4.9Hz,0.5H),4.41(d,J=11.8Hz,1H),4.24(d,J=10.7Hz,0.5H),3.55(ddd,J=10.9,6.9,4.4Hz,1H),3.51–3.40(m,2H),3.03–2.89(m,2H),2.85(d,J=11.9Hz,3H),2.34(q,J=6.6Hz,1H),2.05(ddt,J=16.5,13.4,5.7Hz,2H),1.81–1.74(m,2H),1.63(dddd,J=12.6,9.3,6.2,1.4Hz,2H),1.50–1.41(m,1H),1.39–1.26(m,10H),1.16(dd,J=6.2,3.2Hz,3H),0.98–0.80(m,17H),0.73(d,J=3.6Hz,2H),-0.00–-0.06(m,6H)。13C NMR(101MHz,CDCl3)δ172.9,172.6,170.5,155.4,154.9,154.8,139.2,139.1,136.7,136.4,131.6,131.4,131.3,131.2,129.6,129.5,128.5,128.4,128.4,127.7,127.6,127.6,127.5,126.9,126.9,126.7,79.7,79.7,79.6,77.5,77.2,76.8,76.1,75.5,74.4,74.3,70.4,65.4,60.9,60.5,59.7,59.4,51.9,51.8,51.3,40.2,40.1,39.2,36.5,34.7,34.4,34.0,33.8,33.4,31.3,28.8,28.4,28.3,26.0,25.9,25.1,24.4,19.7,19.5,18.3,18.3,16.0,15.9,14.8,11.3,10.8,-5.3,-5.3,-5.4.HRMS(ESI,m/z)for C45H73N2O7Si+[M+H]+:Calcd.781.5187;Found:781.5182。
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将20(300mg,0.38mmol,1.0eq.)溶解在乙酸乙酯(5mL,0.077M)溶剂中,加入钯/碳(30mg,10% Pd,0.0285mmol,0.042eq.)后,用真空水泵除尽反应体系中的氧气,将反应体系中的气体置换成氢气,在氢气条件下室温搅拌5小时。经TLC监测确认原料转化完全后,反应液经过硅藻土填充的短柱过滤掉固体,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)即可以90%的产率得到无色油状化合物21(268mg,0.34mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色,(c 1.12,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ7.28(dd,J=7.3,3.2Hz,4H),7.25–7.10(m,6H),5.26(d,J=9.0Hz,0.5H),5.23(s,1H),5.17(d,J=9.2Hz,0.5H),4.97(dq,J=8.6,5.1,4.6Hz,1H),4.88(td,J=8.5,6.0Hz,0.5H),4.76(d,J=10.5Hz,0.5H),4.51(d,J=11.8Hz,1H),4.41(d,J=11.8Hz,1H),3.55(dt,J=10.9,5.6Hz,1H),3.49–3.40(m,2H),3.01–2.88(m,2H),2.84(d,J=22.2Hz,3H),1.77(d,J=8.3Hz,1H),1.74–1.59(m,3H),1.57–1.49(m,1H),1.32(d,J=34.0Hz,15H),1.13(dd,J=6.1,1.3Hz,4H),0.94–0.76(m,18H),0.72(d,J=4.1Hz,2H),-0.03(d,J=2.9Hz,6H)。13CNMR(126MHz,CDCl3)δ172.7,170.6,154.9,139.3,136.5,129.6,129.5,128.5,128.3,127.6,127.4,126.8,126.7,79.6,77.4,77.2,76.9,75.9,75.3,74.9,74.9,70.4,65.4,60.9,60.7,59.8,59.6,53.5,51.9,51.2,40.1,36.7,36.6,36.4,34.7,34.3,34.1,33.4,33.1,33.0,32.8,31.3,29.3,28.4,28.3,27.4,26.3,26.0,25.9,25.8,25.1,19.7,19.7,18.2,15.8,15.8,14.7,14.6,11.3,10.8,-5.3,-5.4.HRMS(ESI,m/z)for C45H75N2O7Si+[M+H]+:Calcd.783.5344;Found:783.5338。
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将化合物21(250mg,0.31mmol,1.0eq.)溶解在甲醇(5mL,0.062M)中并冷却至0℃,向反应体系中加入右旋樟脑磺酸14mg,0.062mmol,0.2eq.)。反应体系升温至室温并持续搅拌4小时。经TLC监测确认原料21转化完全后,向反应体系中加入三乙胺(0.1mL),随后将反应液直接真空泵减压浓缩获得粗产物,不经纯化直接用于下一步反应。粗产物溶解在无水的二氯甲烷(5mL,0.07M)中并冷却至0℃,然后加入戴斯马丁试剂(223mg,0.53mmol,1.5equiv.)。反应体系升至室温并持续搅拌2小时,经TLC监测确认转化完全后,在0℃下缓慢加入饱和碳酸氢钠溶液(5mL)将反应淬灭。再加入乙酸乙酯(3×10mL)萃取,合并得到的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/3)即可以73%的产率得到无色油状化合物22(151mg,0.226mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1:3)。紫外荧光&磷钼酸显色,(c 2.9,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ7.35–7.30(m,4H),7.29–7.13(m,6H),5.38(d,J=9.0Hz,1H),5.03–4.96(m,1H),4.88(q,J=8.0Hz,1H),4.83(d,J=10.9Hz,1H),4.55(d,J=11.8Hz,1H),4.44(d,J=11.8Hz,1H),3.54(dt,J=10.9,5.4Hz,1H),3.51–3.44(m,2H),3.04–2.94(m,2H),2.89(d,J=9.4Hz,3H),2.72–2.62(m,1H),1.85(d,J=9.3Hz,1H),1.72(q,J=4.4Hz,2H),1.65–1.53(m,2H),1.37(m,18H),1.17(d,J=6.1Hz,3H),1.12(dd,J=19.3,7.8Hz,1H),0.98–0.82(m,10H),0.76(d,J=4.6Hz,3H)。13C NMR(126MHz,CDCl3)δ172.9,171.1,155.3,139.1,136.3,129.5,129.5,129.4,128.5,128.4,128.3,127.6,127.6,127.5,127.3,126.8,126.6,79.9,75.5,74.8,74.8,70.3,65.1,60.8,58.9,58.6,51.9,51.2,39.4,39.0,36.7,36.6,34.6,34.2,33.2,32.8,32.7,30.9,29.2,28.3,28.3,27.3,27.2,26.3,25.7,24.7,19.6,15.7,14.8,14.6,10.6.HRMS(ESI,m/z)for C39H61N2O7 +[M+H]+:Calcd.669.4479;Found:669.4483。
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称取叔丁醇钾(196mg,1.75mmol,5.0equiv.)于圆底烧瓶中在130℃下抽真空活化9小时,然后加入四氢呋喃(5mL,0.07M)将其溶解,冷却到-78℃加入反式-2-丁烯(137mg,2.45mmol,7.0equiv.)随后逐滴滴加正丁基锂(1.09mL,1.75mmol,1.6M溶解在正己烷中,5.0equiv.)伴随着反应液变成橘黄色。然后升温至-45℃反应30分钟,随后再降温到-78℃。紧接着在手套箱中称取(-)-B-甲氧基二异松莰基硼烷(0.64g,2.1mmol,6.0equiv.)并溶解在四氢呋喃(2mL),逐滴滴加同时反应液变成亮黑色。30分钟后逐滴滴加三氟化硼.乙醚(0.35mL,2.8mmol,8.0equiv.),紧接着将化合物22(233mg,0.35mmol,1.0equiv.)溶解在四氢呋喃(2mL)中逐滴加入。然后在-78℃反应3小时,经TLC监测确认原料转化完全后,用甲醇(5mL)将反应淬灭再恢复室温,经真空泵减压浓缩获得粗产物。再将粗产物溶解在四氢呋喃(6mL)/水(4mL)的混合溶剂中,在室温向其中加入四水合过硼酸钠(270mg,1.75mmol,5.0equiv.),反应体系在室温持续搅拌3小时。用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/3)即可以71%的产率和dr值大于20:1的立体选择性得到无色油状化合物23(180mg,0.25mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,(c 0.57,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ7.32(dd,J=6.4,3.8Hz,4H),7.30–7.14(m,6H),5.91–5.71(m,1H),5.44(d,J=8.8Hz,0.5H),5.21(dd,J=9.2,6.5Hz,0.5H),5.14–5.01(m,3H),5.00–4.94(m,1H),4.88–4.75(m,1H),4.55(d,J=11.8Hz,1H),4.44(d,J=11.8Hz,1H),3.49(h,J=6.0Hz,1H),3.44–3.39(m,1H),3.08–2.93(m,2H),2.89(d,J=22.8Hz,3H),2.31–2.19(m,1H),1.91–1.82(m,1H),1.73–1.52(m,5H),1.44–1.23(m,17H),1.17(d,J=6.1Hz,4H),1.07–1.01(m,4H),1.00–0.80(m,10H),0.75(dd,J=7.5,4.4Hz,3H)。13C NMR(126MHz,CDCl3)δ172.9,170.8,155.4,139.9,139.7,139.3,136.7,129.7,129.6,129.5,129.5,128.5,128.4,127.7,127.7,127.4,126.8,116.6,115.9,79.9,77.4,77.3,77.2,76.9,75.0,74.9,74.7,73.1,72.6,70.4,61.0,60.9,52.4,44.1,43.8,39.5,36.9,36.8,36.3,33.9,33.5,32.8,32.7,31.6,30.9,28.5,28.4,27.5,25.8,24.8,19.8,19.7,16.2,16.1,15.7,14.7,14.2,10.6.HRMS(ESI,m/z)for C43H67N2O7 +[M+H]+:Calcd.723.4948;Found:723.4943。
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将化合物23(230mg,0.32mmol,1.0equiv.)溶解在无水的二氯甲烷(5.0mL,0.064M)中并冷却至0℃,然后依次加入三乙胺(98μL,0.64mmol,2.0equiv.)和叔丁基二甲硅基三氟甲磺酸酯(111μL,0.48mmol,1.5equiv.)。反应体系升至室温并持续搅拌1小时,经TLC监测确认化合物23转化完全后,在0℃下缓慢加入饱和碳酸氢钠溶液(5mL)将反应淬灭。再加入乙酸乙酯(3×5mL)萃取,合并得到的有机相用饱和食盐水溶液(5mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/9)即可以81%的产率得到无色油状化合物24(217mg,0.26mmol)。
TLC:Rf=0.50(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色, (c 0.73,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ7.37–7.30(m,4H),7.29–7.13(m,6H),5.85–5.61(m,1H),5.33–5.25(m,0.5H),5.18(t,J=9.5Hz,0.5H),5.08–4.88(m,4H),4.82(dd,J=12.9,6.7Hz,1H),4.60–4.53(m,1H),4.47–4.41(m,1H),3.54(dtd,J=13.9,7.3,6.6,3.0Hz,1H),3.51–3.39(m,1H),3.07–2.91(m,2H),2.87(s,3H),2.42–2.23(m,1H),2.09–1.77(m,1H),1.69–1.51(m,5H),1.45–1.25(m,17H),1.17(dd,J=6.1,2.5Hz,3H),1.13(d,J=6.1Hz,2H),1.00(d,J=6.8Hz,2H),0.96(d,J=6.9Hz,4H),0.93–0.85(m,14H),0.85–0.79(m,3H),0.78(td,J=6.3,2.5Hz,2H),0.13–-0.02(m,6H)。13C NMR(126MHz,CDCl3)δ173.0,172.7,170.8,170.6,155.5,154.9,140.1,140.0,136.6,129.7,129.5,128.6,128.5,128.4,127.7,127.7,127.5,126.9,126.9,126.8,115.3,79.7,77.4,77.2,76.9,76.2,75.3,75.3,75.0,74.9,74.8,72.7,72.5,70.4,61.0,60.8,52.0,51.9,42.3,42.2,40.4,39.0,37.0,36.8,36.8,36.7,36.3,33.8,33.7,33.1,32.8,31.3,31.3,28.5,28.4,27.6,26.5,26.1,26.0,26.0,25.9,25.9,25.3,24.5,23.3,19.8,19.7,18.2,18.2,17.4,17.3,15.9,14.7,14.5,14.4,11.4,10.9,-4.1,-4.2,-4.3,-4.5,-4.4.HRMS(ESI,m/z)for C49H81N2O7Si+[M+H]+:Calcd.837.5813;Found:837.5814。
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将化合物24(215mg,0.26mmol,1.0equiv.)溶解在无水的二氯甲烷(5.0mL,0.051M)中并冷却至-78℃,然后向反应体系不断通入臭氧,并维持3分钟,直到溶液呈蓝色。后加入三苯基膦(341mg,1.30mmol,5.0equiv.),反应体系升至室温并持续搅拌1小时,经TLC监测确认化合物24转化完全后,将反应液直接旋干,过短柱将三苯基膦除去,产物直接用于下一步。
将化合物上一步产物溶解在二氯甲烷(5mL,0.051M)中并冷却至0℃,然后依次加入2,2,6,6-四甲基哌啶氧化物(16mg,0.10mmol,0.40equiv.)、醋酸碘苯(251mg,0.78mmol,3.0equiv.)和水(1.0mL)。反应体系升至室温并持续搅拌12小时,经TLC监测确认原料转化完全后,在0℃下缓慢加入饱和硫代硫酸钠水溶液(5mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/1)即两步反应以68%的产率得到无色油状化合物25(151mg,0.18mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/3)。紫外荧光&磷钼酸显色,(c 0.92,CHCl3).1H NMR(500MHz,CDCl3)(Mixture of conformers)δ8.03(dd,J=8.0,6.4Hz,1H),7.37–7.29(m,4H),7.21(d,J=5.9Hz,6H),5.35(d,J=9.6Hz,1H),5.13(dq,J=12.5,6.3Hz,1H),4.93(td,J=8.5,6.4Hz,1H),4.74(t,J=9.9Hz,1H),4.56(d,J=11.8Hz,1H),4.45(d,J=11.8Hz,1H),3.97–3.82(m,1H),3.49(q,J=6.0Hz,1H),3.10–2.96(m,2H),2.92(s,3H),2.74(t,J=5.8Hz,1H),1.87–1.79(m,1H),1.77–1.65(m,3H),1.58(ddd,J=15.0,9.7,5.8Hz,2H),1.44–1.26(m,20H),1.17(dtt,J=12.4,8.9,4.9Hz,12H),0.94–0.82(m,17H),0.82–0.69(m,4H),0.10(s,6H)。13C NMR(126MHz,CDCl3)δ176.5,173.0,170.9,170.4,166.2,154.9,139.2,137.6,136.4,132.7,131.0,130.3,129.6,129.4,128.6,128.5,128.5,128.3,127.7,127.6,127.4,127.0,126.8,79.8,75.2,75.0,71.6,71.5,70.4,61.0,52.0,51.8,44.2,44.0,40.2,36.7,36.6,36.1,35.4,33.6,32.5,31.3,28.4,28.3,27.5,27.3,26.6,25.9,25.8,25.8,25.4,20.1,20.1,20.0,19.7,17.9,15.8,14.7,14.1,14.0,11.3,10.7,10.7,-4.3,-4.8,-4.9.HRMS(ESI,m/z)forC48H79N2O9Si+[M+H]+:Calcd.855.5555;Found:855.5557。
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将化合物25(150mg,0.176mmol,1.0equiv.)溶解在无水的二氯甲烷(5.0mL,0.035M)中并冷却至0℃,然后依次加入三乙胺(0.17mL,1.23mmol,7equiv.)和三氟甲磺酸三甲基硅酯(0.16mL,0.88mmol,5equiv.)。反应体系升至室温并持续搅拌3小时,经TLC监测确认化合物25转化完全后,在0℃下缓慢加入饱和碳酸氢钠水溶液(5mL)淬灭反应,并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,粗产物不需经过纯化直接用于下一步。
将上一步粗产物溶解在无水的二氯甲烷(117mL,0.0015M)中并冷却至0℃,然后依次加入N,N-二异丙基乙胺(0.31mL,1.76mmol,10equiv.)、N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(317mg,0.88mmol,5.0equiv.)和N-羟基-7-氮杂苯并三氮唑(72mg,0.528mmol,3.0equiv.)。反应体系升至室温并持续搅拌9小时,经TLC监测确认原料转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(10mL)淬灭反应并用乙酸乙酯(3×20mL)萃取,将合并的有机相用饱和食盐水溶液(20mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/2)即可以两步51%的产率得到无色油状化合物4(66mg,0.09mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=1/1).紫外荧光&磷钼酸显色,(c 0.64,CHCl3).1H NMR(500MHz,CDCl3)δ7.41–7.29(m,4H),7.29–7.16(m,6H),5.76(d,J=10.3Hz,1H),5.23(td,J=10.9,4.5Hz,1H),4.92(d,J=11.7Hz,1H),4.76(ddd,J=11.0,5.2,1.7Hz,1H),4.55(d,J=11.7Hz,1H),4.44(d,J=11.8Hz,1H),4.16(dd,J=8.0,3.2Hz,1H),3.48(q,J=5.9Hz,1H),3.21(t,J=12.0Hz,1H),2.90(dd,J=12.5,4.5Hz,1H),2.56(s,3H),2.52(dd,J=6.7,3.2Hz,1H),1.92(dt,J=7.6,4.0Hz,1H),1.85(ddd,J=11.3,6.6,3.8Hz,1H),1.78–1.67(m,1H),1.60(dt,J=15.5,5.0Hz,2H),1.46–1.35(m,3H),1.32–1.22(m,2H),1.18(d,J=6.1Hz,4H),1.07(d,J=6.6Hz,3H),0.91(d,J=3.2Hz,9H),0.86(d,J=6.4Hz,5H),0.77–0.65(m,7H),0.22(s,3H),0.14(s,3H).13C NMR(126MHz,CDCl3)δ174.5,174.0,168.9,139.2,136.6,129.3,128.7,128.4,127.7,127.4,127.0,76.1,75.0,70.4,68.9,60.6,50.9,48.3,37.3,36.8,33.8,32.7,32.2,30.5,30.1,26.5,26.0,25.7,23.7,19.7,18.2,15.6,15.4,10.0,7.6,-3.7,-3.8.HRMS(ESI,m/z)forC43H69N2O6Si+[M+H]+:Calcd.737.4925;Found:737.4924。
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将4(65mg,0.088mmol,1.0eq.)溶解在乙酸乙酯(3mL,0.029M)中,加入钯/碳(20mg,10% Pd,0.019mmol,0.028eq.)后,用真空水泵除尽反应体系中的氧气,将反应体系中的气体置换成氢气,在氢气条件下室温搅拌9小时。经TLC监测确认原料4转化完全后,反应液经过硅藻土填充的短柱过滤掉固体,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/1)即可以91%的产率得到无色油状化合物26(52mg,0.08mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=1/2)。紫外荧光&磷钼酸显色,(c 0.52,CHCl3).1H NMR(400MHz,CDCl3)δ7.52–6.87(m,5H),5.81(d,J=10.3Hz,1H),5.22(td,J=11.0,4.6Hz,1H),4.92(d,J=11.7Hz,1H),4.85–4.70(m,1H),4.16(dd,J=7.7,3.1Hz,1H),3.77(ddd,J=12.0,8.6,5.3Hz,1H),3.21(t,J=12.0Hz,1H),2.91(dd,J=12.5,4.6Hz,1H),2.56(s,3H),2.52(dd,J=6.7,3.2Hz,1H),1.93(dq,J=7.4,3.6Hz,1H),1.89–1.81(m,1H),1.74(ddd,J=15.8,8.0,1.8Hz,1H),1.61(dd,J=15.7,5.1Hz,2H),1.49–1.35(m,3H),1.34–1.24(m,3H),1.18(d,J=6.1Hz,5H),1.07(d,J=6.7Hz,3H),0.92(s,9H),0.91–0.84(m,3H),0.74(dd,J=11.5,5.9Hz,7H),0.22(s,3H),0.14(s,3H).13C NMR(101MHz,CDCl3)δ173.6,173.1,168.0,135.6,128.3,127.7,126.1,76.4,75.1,68.0,67.2,59.7,50.0,47.3,38.5,36.3,32.8,31.7,31.3,29.6,29.2,25.8,25.1,24.8,22.8,22.7,17.2,14.7,14.5,9.1,6.6,-4.6,-4.8.HRMS(ESI,m/z)forC36H63N2O6Si+[M+H]+:Calcd.647.4455;Found:647.4448。
实施例2
经反应中间体合成环酯肽天然产物colletotrichamide A
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将化合物26(55mg,0.096mmol,1.2equiv.)、2,6-二叔丁基-4-甲基吡啶(43mg,0.208mmol,2.6equiv.)以及活化后的分子筛溶解在无水的二氯甲烷(5.0mL,0.019M)中,并在室温下持续搅拌0.5小时。随后将反应体系冷却至-78℃,将三氟甲磺酸酐(17μL,0.104mmol,1.3equiv.)逐滴加入,并在该温度下搅拌10分钟。随后将化合物3(52mg,0.08mmol,1.0equiv.)溶解在无水的二氯甲烷(3mL)中逐滴加入。然后在-78℃反应4个小时,经TLC监测确认原料转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(5mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=1/6)即可以两步61%的产率得到无色油状化合物27(53mg,0.049mmol)。
TLC:Rf=0.40(薄层硅胶板,乙酸乙酯/正己烷=1/6)。紫外荧光&磷钼酸显色,(c 0.57,CHCl3).1H NMR(500MHz,CDCl3)δ7.59–7.44(m,4H),7.42–7.05(m,16H),5.81(d,J=10.3Hz,1H),5.61(s,1H),5.23(td,J=10.9,4.5Hz,1H),4.98(d,J=12.4Hz,1H),4.92(d,J=11.6Hz,1H),4.86(dd,J=12.5,7.8Hz,1H),4.80–4.74(m,1H),4.76–4.64(m,1H),4.63–4.55(m,1H),4.53(s,1H),4.28(dd,J=10.5,4.8Hz,1H),4.21(t,J=9.6Hz,1H),4.16(dd,J=8.0,3.1Hz,1H),3.93(t,J=10.3Hz,1H),3.88–3.79(m,2H),3.58(dd,J=9.9,3.0Hz,1H),3.30(td,J=9.7,4.8Hz,1H),3.21(t,J=12.0Hz,1H),2.91(dd,J=12.6,4.6Hz,1H),2.56(s,3H),2.52(dd,J=6.7,3.1Hz,1H),2.01–1.91(m,1H),1.86(dt,J=11.8,6.7Hz,1H),1.74(dd,J=15.8,7.8Hz,1H),1.61(dd,J=15.5,5.3Hz,2H),1.44(td,J=11.4,4.9Hz,3H),1.39–1.27(m,3H),1.24–1.16(m,2H),1.13–1.03(m,6H),0.91(s,9H),0.86(d,J=6.4Hz,3H),0.81–0.67(m,7H),0.22(s,3H),0.14(s,3H).13CNMR(101MHz,CDCl3)δ174.5,173.9,168.9,138.7,138.5,137.7,136.5,129.2,128.8,128.6,128.5,128.3,128.1,128.0,127.6,127.5,127.4,126.9,126.1,101.4,100.0,78.7,78.2,76.0,74.7,74.1,72.3,68.9,68.7,67.7,60.6,50.8,48.2,37.3,37.2,33.7,32.6,32.2,30.5,30.0,29.7,26.2,26.0,25.7,25.5,23.7,19.0,18.1,15.5,15.4,9.9,7.5,-3.8,-3.9.HRMS(ESI,m/z)for C63H89N2O11Si+[M+H]+:Calcd.1077.6236;Found:1077.6238。/>
(2)
将化合物27(52mg,0.048mmol,1.0equiv.)溶解在无水的四氢呋喃(3.0mL,0.016M)中并冷却至0℃,然后加入四丁基氟化铵(0.58mL,0.576mmol,12equiv.,1.0M inTHF)。反应体系升至室温并持续搅拌6小时,经TLC监测确认化合物27转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(5mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,粗产物不需经过纯化直接用于下一步。
将上一步所得粗品溶解在甲醇(3mL,0.009M)中,加入钯/碳(25mg,10% Pd,0.024mmol,0.035eq.)后,用真空水泵除尽反应体系中的氧气,将反应体系中的气体置换成氢气,在氢气条件下室温搅拌9小时。经TLC监测确认原料转化完全后,反应液经过硅藻土填充的短柱过滤掉固体,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(甲醇/二氯甲烷=1/10)即可以83%的产率得到白色固体化合物colletotrichamide A(15mg,0.022mmol)。
TLC:Rf=0.30(薄层硅胶板,甲醇/二氯甲烷=1/10)。紫外荧光&磷钼酸显色,(c 0.12,MeOH).1H NMR(400MHz,DMSO)δ8.63(d,J=9.5Hz,1H),7.42–7.04(m,5H),5.20–5.04(m,1H),4.83(d,J=11.6Hz,1H),4.75(s,1H),4.69(d,J=10.5Hz,1H),4.56(d,J=5.8Hz,1H),4.48(s,1H),4.41(s,1H),4.22(s,1H),3.93(s,1H),3.86–3.79(m,1H),3.73(d,J=11.8Hz,1H),3.59(s,1H),3.57–3.44(m,1H),3.32(s,1H),3.14(dd,J=13.0,9.4Hz,2H),3.06(d,J=6.7Hz,3H),2.90(dd,J=12.9,6.2Hz,2H),2.72(s,3H),2.63(dd,J=7.0,3.4Hz,1H),1.91(s,2H),1.58(d,J=6.0Hz,3H),1.51(s,1H),1.48(s,1H),1.31(s,4H),1.11(d,J=6.1Hz,3H),1.06–0.96(m,2H),0.89(d,J=6.8Hz,3H),0.84(d,J=6.4Hz,3H),0.75(dd,J=10.9,5.0Hz,6H).13C NMR(151MHz,DMSO)δ173.5,173.0,168.6,137.7,129.1,128.2,126.4,97.5,77.4,76.0,73.9,72.4,71.3,67.3,67.0,61.5,59.8,49.6,46.3,36.9,35.8,33.5,31.7,31.5,29.8,29.8,26.1,25.3,23.3,19.2,15.6,15.3,9.7,7.5.HRMS(ESI,m/z)for C36H59N2O11 +[M+H]+:Calcd.965.4119;Found:695.4121。
实施例3
经反应中间体合成环酯肽天然产物colletopeptide A
将化合物26(12mg,0.019mmol,1.0eq.)溶解在无水的四氢呋喃(3.0mL,0.006M)中并冷却至0℃,然后加入四丁基氟化铵(0.23mL,0.23mmol,12equiv.,1.0M in THF)。反应体系升至室温并持续搅拌6小时,经TLC监测确认化合物26转化完全后,在0℃下缓慢加入饱和氯化铵水溶液(5mL)淬灭反应并用乙酸乙酯(3×10mL)萃取,将合并的有机相用饱和食盐水溶液(10mL)洗涤,再用无水硫酸钠固体干燥。干燥结束后用砂芯漏斗过滤,滤液经真空泵减压浓缩获得粗产物,利用硅胶柱层析分离(乙酸乙酯/正己烷=4/1)即可以67%的产率得到白色固体colletopeptide A(7mg,0.013mmol)。
TLC:Rf=0.30(薄层硅胶板,乙酸乙酯/正己烷=3/1)。紫外荧光&磷钼酸显色,(c 0.08,MeOD).1H NMR(500MHz,MeOD)δ7.35–7.21(m,4H),7.25–7.15(m,1H),5.26(dd,J=10.7,5.3Hz,1H),4.85(s,1H),4.76(ddd,J=10.6,4.3,2.2Hz,1H),4.55(s,1H),4.04(dd,J=8.3,3.6Hz,1H),3.78–3.57(m,1H),3.22(dd,J=12.8,10.7Hz,1H),2.91(dd,J=12.8,5.3Hz,1H),2.71(s,3H),2.70–2.60(m,1H),2.05–1.92(m,1H),1.94–1.83(m,1H),1.69(ddd,J=15.8,8.4,2.2Hz,1H),1.67–1.60(m,1H),1.63–1.54(m,1H),1.52–1.42(m,1H),1.42–1.34(m,3H),1.36–1.25(m,2H),1.14(d,J=6.1Hz,3H),1.10–1.01(m,1H),1.01(d,J=6.9Hz,3H),0.98–0.92(m,1H),0.86(d,J=6.5Hz,3H),0.80(d,J=6.6Hz,3H),0.79–0.69(m,1H),0.74(d,J=3.5Hz,3H).13C NMR(101MHz,MeOD)δ176.4,175.2,170.1,138.4,130.3,129.6,127.9,77.9,69.1,68.6,62.1,51.8,48.7,40.2,37.4,35.3,33.3,32.7,31.7,30.9,27.6,27.1,24.9,23.5,16.3,15.9,10.3,7.8.HRMS(ESI,m/z)for C30H49N2O6 +[M+H]+:Calcd.533.3591;Found:533.3578。
综上所述,本发明首次合成了活性天然环酯肽colletopeptide A和colletotrichamide A及其反应中间体,克服了目前缺乏高效合成天然环酯肽colletopeptide A和colletotrichamide A的方法的问题,而且,该全合成方法具有工艺简单、成本低和产率高的特点,具有很强的医药工业应用前景。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
1.一种环酯肽类反应中间体,其特征在于,所述反应中间体的结构式如式(I)所示:
所述反应中间体用于制备天然环酯肽colletopeptide A和colletotrichamide A。
2.一种如权利要求1所述的环酯肽类反应中间体的合成方法,其特征在于,包括:
在氟甲磺酸三甲基硅酯和三乙胺的条件下,化合物25脱除Boc基团,再在催化条件下发生大环内酰胺化反应,生成化合物4;
在钯碳的条件下,所述化合物4脱除苄基保护,得到所述反应中间体;
其中,所述化合物25和所述化合物4的结构式如下所示:
3.根据权利要求2所述的环酯肽类反应中间体的合成方法,其特征在于,所述催化采用多肽缩合催化剂和肽偶联剂;
其中,所述多肽缩合催化剂为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU,
和/或,所述肽偶联剂为N-羟基-7-氮杂苯并三氮唑HOAt。
4.根据权利要求2所述的环酯肽类反应中间体的合成方法,其特征在于,所述化合物25的合成路线如下所示:
5.根据权利要求4所述的的环酯肽类反应中间体的合成方法,其特征在于,所述化合物5的合成方法,包括:
在Grubbs II催化剂的条件下,化合物14和化合物11进行交叉烯烃复分解反应,生成化合物5;
所述交叉烯烃复分解反应如下所示:
6.根据权利要求5所述的的环酯肽类反应中间体的合成方法,其特征在于,所述化合物11的合成方法,包括:
在碘化亚铜的催化下,化合物9在格氏试剂烯丙基溴化镁的亲核进攻下开环反应,生成化合物10;
所述化合物10的羟基被苄基保护,得到化合物11;
所述化合物9、10和11的结构式如下所示:
7.一种环酯肽类天然产物的合成方法,其特征在于,经如权利要求1所述的反应中间体反应得到环酯肽类天然产物中的colletopeptide A和colletotrichamide A;
所述环酯肽类天然产物的结构式如下所示:
8.根据权利要求7所述的环酯肽类天然产物的合成方法,其特征在于,包括步骤:
经所述的反应中间体在TBAF的条件下脱除TBS保护基,得到环酯肽colletopeptide A。
9.根据权利要求7所述的环酯肽类天然产物的合成方法,其特征在于,包括步骤:
经所述的反应中间体与化合物3进行糖苷化反应,生成化合物27;
将所述化合物27的TBS保护基进行脱保护,在钯碳加氢的条件下脱除糖苷上的芳基保护基团,得到环酯肽colletotrichamide A;
所述化合物3和化合物27的结构式如下:
10.根据权利要求9所述的环酯肽类天然产物的合成方法,其特征在于,所述化合物3的合成方法,包括步骤:
D-甘露糖、乙酸酐和4-二甲氨基吡啶反应,将羟基保护为乙酸酯,再和对甲苯硫酚在三氟化硼乙醚的介导下反应,生成化合物15;
所述化合物15与甲醇钠进行皂化反应,生成化合物16;
所述化合物16和苯甲醛二甲缩醛发生反应,生成化合物17;
在氢化钠和N,N-二甲基甲酰胺的条件下,所述化合物17与苄化溴反应,生成化合物18;
在间氯过氧苯甲酸的条件下,所述化合物18发生氧化,得到化合物3;
所述化合物3的合成路线如下所示:
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