CN113527388A - 一种β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法 - Google Patents
一种β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法 Download PDFInfo
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- CN113527388A CN113527388A CN202110253978.9A CN202110253978A CN113527388A CN 113527388 A CN113527388 A CN 113527388A CN 202110253978 A CN202110253978 A CN 202110253978A CN 113527388 A CN113527388 A CN 113527388A
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- deoxy
- sugar
- glycosyl donor
- azido
- glycosyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
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- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
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- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
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- 238000006243 chemical reaction Methods 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
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- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
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- 150000003214 pyranose derivatives Chemical class 0.000 description 1
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Classifications
-
- 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
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- 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
-
- 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
-
- 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)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明公开了一种β‑2‑脱氧糖、2‑脱氧‑2‑叠氮糖或葡萄糖苷键立体选择性合成的方法。该方法利用糖基给体上的2‑二苯基乙酰膦基(DPPA)，通过磷氧与糖基受体的羟基之间形成氢键作用，从而形成具有高度面选择性的糖苷键。该方法可以高效控制糖苷化反应的立体选择性，尤其是在合成具有挑战性的β构型的2‑脱氧糖和2‑脱氧‑2‑叠氮糖糖苷上，表现出了巨大的优势。该方法底物适用范围广，操作方便，适合合成多种具有生物活性的糖类分子。DPPA基团能在Ni(OTf)2的温和催化作用下实现化学选择性脱除，从而为进一步合成糖醛酸或者高脱氧糖提供可能。
Description
技术领域
本发明涉及化学合成技术领域，更具体的说是涉及一种β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法。
背景技术
β-2-脱氧糖、2-脱氧-2-氨基糖，其广泛存在于自然界，或药物分子中是构成各种抗生素 (大环内酯类、蒽环类、红霉素和烯二炔类)以及强心苷、C21甾体皂苷、透明质酸等糖类化合物的重要结构单元。由于该类化合物具有众多的药理活性，因此，高效合成β-2-脱氧糖、2- 脱氧-2-氨基糖对新药开发具有重大的指导意义。
由于糖环上2位缺少邻基参与基团，糖苷键构型主要是由异头物效应控制，主要得要热力学稳定的α异构体。此外糖环上2位缺少吸电子基团，异头碳电子云密度较高，使2-脱氧糖苷键不稳定，对酸敏感，容易水解或异头位异构化从而需要在温和的条件下进行糖苷化和脱除保护基操作。尽管2-脱氧-2-氨基糖的合成可以使用Phth保护基，但该保护基较为敏感，对其它一些保护不兼容。对于β-2-脱氧糖合成方法主要有SN2或类似SN2反应，I2氧化活化以及糖的构像控制等方法。但这些方法大都操作复杂，条件剧烈或者底物适用性较差等。
氢键介导的分子内苷元递送，能巧妙的避开糖环上2位缺少邻基参与基团的缺点，可以获得优秀的面选择性。
发明内容
针对现有技术存在的上述不足，本发明的目的在于提供一种β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法，解决现有方法对该类糖苷键立体选择性差和底物适用性不佳等问题。
为了达到上述目的，本发明采用如下技术方案：一种β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，将糖基给体、糖基受体及新鲜活化的分子筛加入有机溶剂中常温搅拌0.5～1.5h，然后在将反应体系置于相应温度下，加入催化剂反应完全为止；反应完全后用三乙胺淬灭，经过滤和真空浓缩，柱层析后即得到相应的糖苷；其反应通式如下：
其中，X选自H、N3或OBn；m为1或0；Y为C或C＝O；n为1、2或3；yy为1或2。
在本发明的一些实施例中，糖基给体为吡喃型糖类或呋喃型糖类的葡萄糖、半乳糖、甘露糖、叠氮糖或2-去氧糖(X＝H,N3 or OBn)。
在本发明的一些实施例中，糖基给体保护基(PG)为苄基(Bn)、对甲氧基苄基(PMB)、乙酰基(Ac)、烯丙基(All)或叔丁基二甲基硅醚(TBS)的任意一种或两种，优选为苄基。
在本发明的一些实施例中，糖基给体的离去基团(Le)为N-苯基-三氟乙酰亚胺酯、三氯乙酰亚胺酯、硫苷(CAS号：1384270-00-1)或邻炔基苯甲酸酯中的一种，优选为N-苯基-三氟乙酰亚胺酯或三氯乙酰亚胺酯。
在本发明的一些实施例中，反应中催化剂为TMSOTf、TBSOTf、TfOH、BF3·Et2O或PPh3AuNTf2中的一种，优选为TMSOTf或TBSOTf。
在本发明的一些实施例中，反应溶剂为二氯甲烷、甲苯、三氟甲苯、氯苯、***或乙腈中的一种，优选为三氟甲苯或氯苯。
在本发明的一些实施例中，温度为-78℃～25℃，优选为-25℃～25℃。
在本发明的一些实施例中，分子筛为
MS、
MS或
MS。
在本发明的一些实施例中，所述糖基给体6-位安装的氧化磷侧链，可以是醚键型或者是酯键型(Y＝C or C＝O)优选为酯键型。氧化磷侧链的安装不局限于6位羟基，同样适用于 2-OH,3-OH和4-OH。
在本发明的一些实施例中，所述糖基给体与氧化磷相连的芳香环(Ar)可以是苯环，取代苯环或杂环，优选为苯环。在一些实施例中，取代基选自甲基、溴或氯；杂环为吡啶、咪唑、嘧啶或吡咯。
在本发明的一些实施例中，n可以为0,1,2,3，优选为n＝1。
在本发明的一些实施例中，所述糖基给体I和所述糖基受体ROH的摩尔比为(1.2～2)： (1～1.5)。
在本发明的一些实施例中，所述糖基受体ROH与有机溶剂的摩尔体积比为0.02～0.1mol/L。
在本发明的一些实施例中，催化剂的摩尔加入量为糖基供体摩尔量的5％～100％。
在本发明的一些实施例中，优选的给体中，结构式Ⅰ为以下任一结构的化合物：
本发明的糖基受体可以根据目标化合物进行常规选择。
本发明还提供一种如式I所示的用于β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的糖基给体，
其中各基团定义如前所述。
本发明还公开了式I所示的用于β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的糖基给体6-位安装的氧化磷侧链合成通法，如下式：
在一些实施例中，具体步骤为：将I-a与I-b溶于DMSO中，然后加入50％KOH水溶液，然后在40-60℃下反应1-2h，反应完全后，调pH为1-2，析出白色晶体，过滤即得I-c。
在一些实施例中，I-a与I-b的摩尔比为1.1：1。
本发明还公开了一些典型糖苷化给体中间体的制备方法，如下式：
在一些实施例中，具体步骤为：
(1)将化合物e和对甲氧基苯酚溶于DCM中。在将反应置于冰浴中，温度降低至0℃时缓慢滴加BF3·Et2O。滴加完毕后撤去冰浴，常温搅拌反应。反应完毕后加入三乙胺淬灭反应，旋干，进行硅胶柱层析得硫苷产物为黄色油状液体。将上述产物溶于DCM/MeOH中加甲醇钠，调Ph＝12,常温搅拌反应。在反应完毕后加入阳离子交换树脂调Ph＝7,过滤旋干，在进行硅胶柱层析得产物f白色固体。
(2)将化合物g,相应酸,DMAP溶于DCM中，N2保护。常温下搅拌5min然后再加入EDCI室温搅拌反应过夜。进行硅胶柱层析得化合物h为无色油状液体。
(3)将化合物h溶于THF中，然后加入三苯基膦溴化氢搅拌反应10min后加入H2O 然后室温搅拌4h。反应结束后加入三乙胺淬灭反应。柱色谱分离得产物i为白色固体。
本发明还公开了另一些典型糖苷化给体的制备方法，如下式：
或者为：
在一些实施例中，优化的糖基给体制备的方法包括以下步骤：
(1)室温下将相应的醇与酸溶于干燥的二氯甲烷中；
(2)在惰性气体气氛下，加入DMAP搅拌5min后再加入EDCI，搅拌至TLC显示反应完全；
(3)将混合物真空浓缩后进行硅胶柱层析得到6-位安装的氧化磷侧链硫苷化合物；
(4)上述化合物在NIS和TFA作用下脱除硫苷得到相应的半缩醛，对2-去氧糖，则是利用三苯基溴化氢作用于糖烯得到相应的半缩醛；
(5)得到的相应半缩醛化合物溶于丙酮中以碳酸钾作为碱与N-苯基-三氟乙酰氯反应生产相应的糖基给体。
在一些实施例中，优选的，β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法中，糖苷化产物包括以下部分结构：
本发明所述的糖基给体和糖基供体均表示同样的意思。
相比现有技术，本发明具有如下有益效果：
(1)开发了一种易于合成2-二苯基乙酰膦基(DPPA)基团，该基团可以通过利用分子内苷元递送，以高面选择性来合成β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷。
(2)DPPA基团易于安装到糖的6-位羟基，并且可以利用催化量的Ni(OTf)2能化学选择性的脱除，不影响乙酰基，苄基等。催化量的Ni(OTf)2能化学选择性的脱除具有很高的灵活性及普适性，对合成天然糖苷及其衍生物具有非常重要的意义。
(3)该方法合成高效合成β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键，反应条件温和，底物适用范围广。
(4)该方法可以进一步延伸合成1,6-β-糖苷键的寡糖，糖醛酸以及2,6-二-去氧糖。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
本发明式Ⅲ中的所有化合物按照下述路线一制备：
将亚酰酯给体(1.2eq,20mM)、受体(1.0eq)溶解到干燥PhCF3中，然后加入活化的
分子筛，氮气保护下，室温下搅拌1h。将反应混合物冷却至-25℃，加入TMSOTf(0.12eq)。关闭低温，继续搅拌，直到TLC显示起始物料消耗完毕。用Et3N淬灭后，对混合物进行过滤浓缩。通过硅胶柱层析分离得到相应的产物。未有特殊说明下述糖苷的制备都是遵从路线一。
实施例1化合物Ⅲ-1
将供体Ⅰ-2(50mg,0.06mmol)和相应受体(14mg,0.05mmol)，溶于2mL干燥甲苯中，以TMSOTf(1.4μL,0.006mmol)为催化剂，得到化合物Ⅲ-1(41mg,93％,β/α>20:1)，为白色固体:1H NMR(500MHz,CDCl3)δ7.81–7.74(m,5H),7.51–7.39(m,10H),7.34–7.26(m,13H),7.18(d,J＝7.8Hz,2H),5.56(d,J＝5.0Hz,1H),5.50(d,J＝5.0Hz,1H),5.03(d,J＝11.2Hz,1H),4.95(d,J＝11.0Hz,1H),4.77–4.71(m,3H),4.59(dd,J＝7.9,2.3Hz,1H),4.42(d,J＝10.9 Hz,1H),4.37(d,J＝7.8Hz,1H),4.31(dd,J＝4.9,2.3Hz,1H),4.25–4.21(m,2H),4.14(dd,J＝ 11.8,3.6Hz,1H),4.06(dd,J＝11.4,3.6Hz,2H),3.68(dd,J＝11.6,8.5Hz,1H),3.59–3.54(m, 1H),3.49(dd,J＝12.7,10.7Hz,2H),3.33(dd,J＝20.7,11.9Hz,3H),1.72(s,3H),1.50(s,3H), 1.44(s,3H),1.31(s,3H),1.31(s,3H)；13C NMR(125MHz,CDCl3)δ165.8,165.8,138.7,138.6, 137.9,132.3,132.3,131.5,131.4,131.2,131.2,131.1,131.1,128.8,128.7,128.7,128.6,128.4, 128.3,128.2,128.1,127.8,127.8,127.5,109.4,108.6,104.3,96.4,84.4,81.2,77.2,77.1,75.5,74.9, 74.3,72.6,71.4,70.8,70.5,69.8,67.3,64.1,39.2,39.2,38.7,26.1,26.0,25.0,24.4；HRMS(ESI) calcd forC53H59O13PNa[M+Na]+957.3585,found 957.3574.
实施例2化合物Ⅲ-2
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(8.2mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.68μL,0.0031mmol)为催化剂，得到化合物Ⅲ-2(26mg,94％,β/α>20:1)，为白色固体：1H NMR(500MHz,CDCl3)δ7.83(dd,J＝11.6,7.5Hz,4H),7.56–7.49(m,6H), 7.41–7.33(m,8H),7.27–7.22(m,2H),5.59(d,J＝5.0Hz,1H),4.94(d,J＝10.9Hz,1H),4.78(dd,J＝16.4,10.9Hz,2H),4.65(dd,J＝7.9,2.2Hz,1H),4.50(d,J＝10.9Hz,1H),4.40(d,J＝7.9Hz, 1H),4.36(dd,J＝5.0,2.3Hz,1H),4.30(dd,J＝14.4,6.6Hz,2H),4.20(dd,J＝11.9,4.0Hz,1H), 4.11–4.02(m,2H),3.78(dd,J＝11.1,6.8Hz,1H),3.57–3.50(m,2H),3.42–3.33(m,4H),1.59(s, 3H),1.47(s,3H),1.39(s,3H),1.37(s,3H)；13C NMR(125MHz,CDCl3)δ166.0,166.0,138.3, 138.0,132.6,132.5,132.4,131.6,131.4,131.4,131.3,131.3,129.1,129.0,128.9,128.7,128.7, 128.3,128.2,128.2,128.1,109.6,108.9,102.5,96.6,83.2,77.2,75.2,73.0,71.5,71.0,70.8,69.1, 67.9,66.5,64.0,39.4,38.9,26.3,26.2,25.2,24.6；HRMS(ESI)calcd for C46H52N3O12PNa [M+Na]+892.3181,found892.3185.
实施例3化合物Ⅲ-3
将供体Ⅰ-5(30mg,0.042mmol)和相应受体(9.2mg,0.035mmol),溶于2mL干燥甲苯中，以TMSOTf(0.68μL,0.0031mmol)为催化剂，得到化合物Ⅲ-3(27mg,92％,β/α＝10:1),为白色固体:1H NMR(300MHz,CDCl3)δ7.79(dd,J＝12.0,5.7Hz,4H),7.48(dd,J＝7.5,2.9Hz,6H),7.31(dd,J＝10.5,5.1Hz,8H),7.25–7.22(m,2H),5.55(d,J＝5.0Hz,1H),5.50(d,J＝5.2 Hz,1H),4.83–4.77(m,1H),4.68–4.62(m,1H),4.59(dd,J＝8.0,2.4Hz,1H),4.54(d,J＝11.6Hz, 1H),4.45(dd,J＝9.5,6.0Hz,2H),4.31(dd,J＝5.0,2.3Hz,1H),4.24–4.14(m,3H),3.99(dd,J＝ 11.9,3.3Hz,2H),3.61(dd,J＝11.8,8.4Hz,2H),3.53(d,J＝4.6Hz,1H),3.48(d,J＝4.4Hz,1H), 3.31–3.27(m,2H),2.43(dd,J＝11.7,4.7Hz,1H),1.59(d,J＝11.9Hz,1H),1.54(s,3H),1.43(s, 3H),1.34(s,3H),1.31(s,3H)；13C NMR(125MHz,CDCl3)δ165.9,138.2,138.2,132.2,131.2, 131.2,131.1,131.1,128.8,128.7,128.7,128.6,128.4,128.4,128.2,127.8,127.7,109.4,108.6, 100.4,96.4,79.2,77.2,74.8,72.9,71.4,71.1,70.7,70.5,68.9,67.7,64.5,39.2,38.7,36.3,26.1, 26.0,25.0,24.4；HRMS(ESI)calcd for C46H53O12PNa[M+Na]+851.3167,found 851.3164.
实施例4化合物Ⅲ-4
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(15mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-4(32mg,93％,βonly),为白色固体:[α]D 20＝23.5(c＝0.2in CHCl3)；1H NMR(500MHz,CDCl3)δ7.96(d,J＝7.3Hz,2H),7.90(d,J＝7.3Hz,2H),7.83(d,J＝7.3Hz,2H),7.78–7.73(m,4H),7.50–7.27(m,28H),7.20–7.16(m, 2H),6.19–6.13(m,1H),5.51–5.47(m,1H),5.25(dd,J＝10.2,3.6Hz,1H),5.20(d,J＝3.6Hz, 1H),5.04(d,J＝10.9Hz,1H),4.91(d,J＝11.0Hz,1H),4.77–4.67(m,3H),4.41(dd,J＝16.2,9.3 Hz,2H),4.38–4.32(m,1H),4.19–4.08(m,2H),4.03(dd,J＝11.1,1.9Hz,1H),3.77(dd,J＝11.1, 7.1Hz,1H),3.61–3.54(m,1H),3.43(dd,J＝16.5,11.5Hz,2H),3.38(s,3H),3.37–3.34(m,1H), 3.31(t,J＝7.1Hz,2H)；13C NMR(125MHz,CDCl3)δ165.8,165.8,165.7,165.7,165.5,138.6, 138.4,137.8,133.5,133.4,133.1,132.4,132.2,132.2,131.6,131.4,131.2,131.1,131.0,129.9, 129.9,129.7,129.3,129.1,128.9,128.8,128.7,128.7,128.6,128.5,128.4,128.3,128.3,128.2, 128.1,127.9,127.8,127.7,127.6,103.9,96.9,84.4,82.0,75.6,74.9,74.8,72.6,72.1,70.5,70.0, 69.0,68.8,64.1,55.6,38.9,38.4；HRMS(ESI)calcd for C69H65O16PNa[M+Na]+1203.3902,found1203.3900.
实施例5化合物Ⅲ-5
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(16mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.68μL,0.0031mmol)为催化剂，得到化合物Ⅲ-5(31mg,88％,βonly),为白色固体：[α]D 20＝-52.3(c＝0.1in CHCl3)；1H NMR(500MHz,CDCl3)δ7.98(d,J＝7.3Hz,2H),7.94 (d,J＝7.3Hz,2H),7.85(d,J＝7.3Hz,2H),7.75(dd,J＝20.2,8.1Hz,4H),7.51–7.29(m,23H), 7.19(d,J＝6.5Hz,2H),6.20–6.14(m,1H),5.59–5.53(m,1H),5.29–5.22(m,2H),4.90(d,J＝ 10.8Hz,1H),4.74(dd,J＝22.6,10.9Hz,2H),4.44(d,J＝10.9Hz,1H),4.32–4.26(m,2H),4.20 (d,J＝11.3Hz,1H),4.13(dd,J＝11.9,4.0Hz,1H),4.02(d,J＝9.8Hz,1H),3.70(dd,J＝11.4, 6.2Hz,1H),3.50(s,3H),3.47–3.30(m,6H)；13C NMR(125MHz,CDCl3)δ165.8,165.8,165.7, 165.6,165.5,137.9,137.6,133.5,133.3,133.1,132.3,132.2,131.5,131.1,131.1,131.0,131.0, 129.9,129.9,129.7,129.3,129.1,128.9,128.8,128.7,128.6,128.5,128.5,128.4,128.3,128.0, 128.0,127.9,127.9,102.3,97.0,82.9,77.2,75.5,75.0,72.8,72.1,70.4,69.7,68.9,68.4,66.4,63.7, 55.7,38.9,38.4；HRMS(ESI)calcd for C62H58N3O15PNa[M+Na]+1138.3498,found 1138.3495.
实施例6化合物Ⅲ-6
将供体Ⅰ-5(30mg,0.042mmol)和相应受体(17.7mg,0.035mmol),溶于2mL干燥甲苯中，以TMSOTf(0.78μL,0.0035mmol)为催化剂，得到化合物Ⅲ-6(34mg,89％,β/α>20:1), 为白色固体:1H NMR(600MHz,CDCl3)δ7.98(d,J＝7.2Hz,2H),7.91(d,J＝7.1Hz,2H),7.86 (d,J＝7.2Hz,2H),7.78–7.73(m,4H),7.53–7.40(m,10H),7.39–7.28(m,13H),7.24–7.20(m,2H),6.18–6.12(m,1H),5.62–5.58(m,1H),5.28(dd,J＝10.2,3.7Hz,1H),5.24(d,J＝3.6Hz, 1H),4.81(d,J＝10.8Hz,1H),4.70(d,J＝11.6Hz,1H),4.57(d,J＝11.6Hz,1H),4.44(d,J＝ 10.9Hz,1H),4.36–4.30(m,1H),4.19(m,3H),4.08–4.02(m,1H),3.63–3.52(m,2H),3.50–3.38 (m,5H),3.28–3.18(m,2H),2.49–2.37(m,1H),1.61(m,1H).13C NMR(151MHz,CDCl3)δ165.9, 165.8,165.4,138.2,138.1,133.5,133.4,133.1,132.3,132.3,132.3,132.2,132.1,132.0,131.4, 131.3,131.2,131.1,131.1,131.1,129.9,129.8,129.7,129.2,129.1,128.9,128.8,128.7,128.6, 128.5,128.5,128.4,128.4,128.3,128.2,128.1,127.9,127.8,127.8,127.7,100.7,97.0,79.1,74.9, 72.9,72.0,71.2,70.6,69.2,68.6,67.8,64.4,55.6,38.9,38.5,36.1；HRMS(ESI)calcd for C62H59O15PNa[M+Na]+1097.3484,found 1097.3477.
实施例7化合物Ⅲ-7
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(15mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-7(29mg,90％,βonly),为白色固体:[α]D 20＝18.2(c＝0.2in CHCl3)；1H NMR(500MHz,CDCl3)δ7.72–7.67(m,4H),7.46–7.32 (m,6H),7.28–7.18(m,13H),7.15–7.06(m,2H),5.28(d,J＝5.0Hz,1H),4.86(dd,J＝16.1,11.0 Hz,2H),4.71–4.61(m,3H),4.40–4.29(m,3H),4.15(d,J＝11.1Hz,1H),4.05(dd,J＝11.7,4.0 Hz,1H),3.55–3.20(m,9H),2.32(dd,J＝13.2,2.8Hz,1H),2.26–2.21(m,1H),1.97–1.68(m,7H), 1.61–1.37(m,10H),1.27–1.20(m,3H),1.12(dd,J＝12.5,4.9Hz,1H),1.06–1.00(m,1H),0.96(s, 3H),0.90(d,J＝7.0Hz,3H),0.72(d,J＝5.6Hz,6H)；13CNMR(125MHz,CDCl3)δ165.9,165.8, 140.6,138.6,138.5,137.9,132.3,132.3,131.4,131.2,131.2,131.1,131.1,128.8,128.7,128.7, 128.7,128.4,128.4,128.4,128.3,128.1,127.9,127.8,127.8,127.6,121.8,109.3,102.1,84.7,82.1, 80.9,79.7,77.3,75.6,74.9,72.5,66.9,64.2,62.2,56.6,50.2,41.7,40.3,39.8,39.2,39.1,38.7,37.3,37.0,32.1,31.9,31.5,31.5,30.4,29.9,29.7,28.9,20.9,19.5,17.2,16.3,14.6；HRMS(ESI)calcd for C68H81O10PNa[M+Na]+1111.5460,found 1111.5464.
实施例8化合物Ⅲ-8
将供体Ⅰ-4(30mg,0.031mmol)和相应受体(13.0mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.70μL,0.0038mmol)为催化剂，得到化合物Ⅲ-8(25.9mg,81％,βonly),为白色固体:[α]D 20＝42.1(c＝0.1in CHCl3)；1H NMR(500MHz,Chloroform-d)δ7.86–7.72(m,4H),7.55–7.43(m,6H),7.37–7.28(m,8H),7.23–7.17(m,2H),5.38(d,J＝4.9Hz,1H),4.88(d,J ＝10.8Hz,1H),4.74(dd,J＝16.1,10.9Hz,2H),4.48–4.38(m,2H),4.31(d,J＝7.6Hz,1H), 4.27–4.19(m,1H),4.13(dd,J＝11.9,4.2Hz,1H),3.54–3.29(m,9H),2.42–2.30(m,2H), 2.07–1.95(m,2H),1.93–1.65(m,10H),1.57–1.40(m,6H),1.22–1.08(m,4H),1.03(s,3H),0.98 (d,J＝6.9Hz,3H),0.79(s,6H)；13C NMR(125MHz,CDCl3)δ165.8,165.7,140.4,137.9,137.6, 132.3,132.3,132.3,132.2,131.4,131.1,131.0,128.8,128.7,128.6,128.5,128.4,128.1,128.0, 127.9,127.9,121.9,109.3,100.6,83.0,80.8,79.8,75.4,74.9,72.6,66.9,66.2,63.8,62.1,56.5, 50.1,41.6,40.3,39.8,39.1,38.7,38.6,37.2,36.9,32.1,31.9,31.4,30.3,29.7,29.6,28.8,20.9,19.4, 17.1,16.3,14.5；HRMS(ESI)calcd for C61H74N3O9PNa[M+Na]+1046.5055,found 1046.5058.
实施例9化合物Ⅲ-9
将供体Ⅰ-5(30mg,0.039mmol)和相应受体(13.8mg,0.033mmol),溶于2mL干燥甲苯中，以TMSOTf(0.74μL,0.004mmol)为催化剂，得到化合物Ⅲ-9(27.8mg,85％,βonly),为白色固体:[α]D 20＝-130.8(c＝0.1in CHCl3)；1H NMR(500MHz,CDCl3)δ7.84–7.75(m,4H),7.53–7.44(m,6H),7.36–7.28(m,8H),7.25–7.22(m,2H),5.35(d,J＝5.5Hz,1H),4.82(d,J＝11.0Hz,1H),4.67(d,J＝11.7Hz,1H),4.57(d,J＝11.6Hz,1H),4.53–4.44(m,2H),4.41(q,J＝ 7.5Hz,1H),4.22(d,J＝11.7Hz,1H),4.17(dd,J＝11.7,3.7Hz,1H),3.65–3.57(m,1H), 3.53–3.44(m,4H),3.41–3.35(m,1H),3.31–3.24(m,2H),2.33–2.18(m,3H),2.04–1.94(m,2H), 1.90–1.71(m,7H),1.70–1.63(m,2H),1.57–1.41(m,7H),1.23–1.04(m,4H),1.01(s,3H),0.97(d, J＝7.0Hz,3H),0.80–0.77(m,6H)；13C NMR(125MHz,CDCl3)δ165.9,165.8,140.7,138.2, 138.1,132.3,132.3,132.2,132.2,131.4,131.2,131.1,128.8,128.7,128.7,128.6,128.4,128.4, 128.2,127.8,127.7,127.7,121.6,109.3,97.9,80.8,79.4,78.2,77.4,77.2,74.8,72.8,71.2,66.9, 64.5,62.1,56.5,50.1,41.6,40.3,39.8,39.2,38.9,38.7,37.3,37.0,36.9,32.1,31.9,31.4,31.4,30.3, 29.7,29.6,28.8,20.8,19.4,17.1,16.3,14.5；HRMS(ESI)calcd for C61H75O9PNa[M+Na]+ 1005.5041,found1005.5044.
实施例10化合物Ⅲ-10
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(4.5mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-10(22mg,90％,βonly),为白色固体:[α]D 20＝-16.8(c＝0.1in CHCl3)；1H NMR(300MHz,CDCl3)δ7.85–7.71(m,4H),7.52–7.42(m,6H),7.36–7.27(m,13H),7.21-7.16(m,2H),4.93(dd,J＝11.0,1.6Hz,2H),4.79–4.65(m,3H),4.41(dd,J＝11.5,9.4Hz,2H),4.22(dd,J＝11.7,1.8Hz,1H),4.11(dd,J＝ 11.6,4.5Hz,1H),3.60–3.23(m,7H),2.32–2.17(m,1H),2.12(d,J＝12.2Hz,1H),1.65(dd,J＝ 9.5,3.6Hz,2H),1.04–0.80(m,11H),0.72(d,J＝6.8Hz,3H)；13C NMR(125MHz,CDCl3)δ 165.8,165.8,138.8,138.5,138.0,132.4,132.3,132.3,132.3,132.2,131.6,131.4,131.2,131.1, 131.1,131.1,128.8,128.7,128.7,128.6,128.4,128.3,128.1,127.8,127.7,127.5,100.7,84.8,81.8, 78.0,77.7,77.2,75.5,74.9,74.7,72.3,64.3,48.1,41.0,39.0,38.6,34.4,31.5,25.3,23.3,22.2,21.0, 15.8；HRMS(ESI)calcd forC51H59O8PNa[M+Na]+853.3840,found 853.3845.
实施例11化合物Ⅲ-11
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(4.9mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.70μL,0.0038mmol)为催化剂，得到化合物Ⅲ-11(20.8mg,87％,βonly), 为白色固体:1H NMR(300MHz,CDCl3)δ7.88–7.77(m,4H),7.61–7.47(m,6H),7.46–7.30(m,11H),7.29–7.23(m,2H),4.93(d,J＝10.9Hz,1H),4.85–4.75(m,2H),4.51(d,J＝10.9Hz,1H), 4.35–4.25(m,2H),4.17(dd,J＝11.8,3.9Hz,1H),3.62–3.25(m,7H),2.31–2.20(m,1H),2.11(d, J＝12.7Hz,1H),1.72–1.65(m,2H),1.14–0.87(m,11H),0.75(d,J＝6.9Hz,3H)；13C NMR(125 MHz,CDCl3)δ165.7,165.7,138.0,137.7,132.4,132.4,132.3,132.2,132.2,131.1,131.0,131.0, 128.8,128.7,128.6,128.5,128.4,128.0,127.9,127.9,127.8,99.3,83.1,78.3,77.5,75.3,75.0,72.4, 66.2,64.0,47.7,40.2,38.9,38.4,34.3,31.5,25.2,23.1,22.3,20.9,15.7；HRMS(ESI)calcd for C44H52N3O7PNa[M+Na]+788.3435,found 788.3421.
实施例12化合物Ⅲ-12
将供体Ⅰ-5(30mg,0.039mmol)和相应受体(5.2mg,0.033mmol),溶于2mL干燥甲苯中，以TMSOTf(0.74μL,0.004mmol)为催化剂，得到化合物Ⅲ-12(23.0mg,95％,β/α>20:1),为白色固体:1H NMR(500MHz,CDCl3)δ7.83–7.77(m,4H),7.61–7.47(m,6H),7.38–7.31(m,8H),7.27–7.25(m,2H),4.85(d,J＝11.2Hz,1H),4.72(d,J＝10.7Hz,1H),4.68(d,J＝6.6Hz, 1H),4.58(d,J＝11.6Hz,1H),4.50(d,J＝11.0Hz,1H),4.24–4.19(m,1H),4.17–4.11(m,1H), 3.69–3.62(m,1H),3.53(d,J＝13.8Hz,1H),3.47(d,J＝15.6Hz,2H),3.30(d,J＝6.6Hz,2H), 2.23–2.18(m,1H),2.17–2.12(m,3H),1.85–1.81(m,2H),1.78–1.75(m,3H),1.68–1.60(m,8H)；13C NMR(125MHz,CDCl3)δ165.9,165.9,138.3,138.2,132.3,132.2,132.2,131.2,131.2,131.1, 131.1,131.1,131.1,128.8,128.7,128.7,128.6,128.4,128.4,128.3,128.2,128.1,127.7,127.7, 127.5,92.6,79.8,77.6,74.9,74.7,72.5,71.2,64.8,42.5,42.4,39.3,38.8,37.8,36.3,36.3,30.7, 30.6；HRMS(ESI)calcd forC44H53O7PNa[M+Na]+747.3421,found 747.3424.
实施例13化合物Ⅲ-13
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(11mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-13(29mg,93％,β/α＝3.5:1),为白色固体:Ⅲ-13-:[α]D 20＝-13.9(c＝0.1in CHCl3)；1H NMR(300MHz,CDCl3)δ 7.81–7.73(m,4H),7.47(d,J＝3.4Hz,8H),7.38–7.20(m,23H),5.57(s,1H),5.04(d,J＝11.4Hz, 1H),4.93(d,J＝11.0Hz,1H),4.86(d,J＝3.6Hz,1H),4.82(s,1H),4.80–4.68(m,4H),4.64(d,J＝10.7Hz,1H),4.41(d,J＝10.9Hz,1H),4.36–4.23(m,2H),4.14–4.05(m,2H),3.94–3.86(m, 1H),3.84–3.74(m,2H),3.68(dd,J＝17.2,8.0Hz,1H),3.60–3.44(m,4H),3.42(s,3H),3.29(dd, J＝15.7,7.6Hz,2H)；13C NMR(125MHz,CDCl3)δ165.7,165.7,138.5,138.4,137.8,137.4, 132.3,132.3,132.3,132.2,132.1,131.4,131.3,131.1,131.1,131.0,131.0,128.9,128.8,128.7, 128.7,128.6,128.4,128.3,128.2,128.1,128.1,128.1,127.8,127.8,127.5,127.5,127.4,126.0, 104.1,101.3,100.2,84.4,82.8,81.5,78.4,78.2,77.2,77.1,75.5,75.0,74.8,74.4,72.6,69.2,63.9, 62.2,55.3,39.1,38.6；HRMS(ESI)calcd for C62H63O13PNa[M+Na]+1069.3898,found 1069.3903.
Ⅲ-13-:[α]D 20＝50.1(c＝0.1in CHCl3)；1H NMR(300MHz,CDCl3)δ7.77–7.67(m,4H), 7.52–7.29(m,26H),7.21–7.17(m,2H),7.12–7.08(m,1H),7.03–6.98(m,2H),5.57(s,1H),5.01 (d,J＝10.9Hz,1H),4.85(d,J＝4.6Hz,2H),4.84–4.77(m,3H),4.73–4.68(m,3H),4.37–4.27(m, 2H),4.13–3.95(m,4H),3.95–3.70(m,4H),3.67–3.61(m,1H),3.46(s,3H),3.45–3.37(m,3H), 3.30–3.27(m,1H)；13C NMR(125MHz,CDCl3)δ165.7,165.7,139.0,138.5,138.0,137.5,132.3, 131.2,131.1,131.0,129.0,128.8,128.8,128.8,128.7,128.7,128.6,128.4,128.4,128.3,128.1, 128.0,128.0,127.9,127.8,127.6,126.1,101.4,97.4,94.4,82.6,82.0,79.1,77.3,76.9,75.8,75.6, 75.0,74.6,73.0,69.1,68.6,63.5,62.4,55.1,39.0,38.6；HRMS(ESI)calcd for C62H63O13PNa [M+Na]+1069.3898,found1069.3900.
实施例14化合物Ⅲ-14
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(12mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.70μL,0.0038mmol)为催化剂，得到化合物Ⅲ-14(28mg,90％,βonly),为白色固体:[α]D 20＝-30.1(c＝0.2in CHCl3)；1H NMR(500MHz,CDCl3)δ7.79–7.72(m,4H),7.50–7.28(m,24H),7.20(d,J＝6.4Hz,2H),5.56(s,1H),4.90(d,J＝10.7Hz,1H),4.86(d,J＝ 11.1Hz,1H),4.83(d,J＝3.6Hz,1H),4.78(d,J＝10.8Hz,1H),4.72(d,J＝10.9Hz,1H),4.46 (dd,J＝16.8,9.4Hz,2H),4.34–4.27(m,2H),4.10–4.05(m,2H),3.89–3.85(m,1H),3.75–3.70(m, 2H),3.66–3.60(m,1H),3.54–3.41(m,3H),3.40(s,3H),3.39–3.29(m,3H),3.27–3.21(m,1H)；13C NMR(125MHz,CDCl3)δ165.7,138.6,137.8,137.5,137.4,132.4,132.3,131.1,131.0,128.9, 128.9,128.8,128.7,128.5,128.5,128.3,128.2,128.1,128.0,128.0,128.0,127.9,127.6,126.0, 102.9,101.4,100.1,83.2,82.7,79.6,77.7,77.2,77.2,75.5,75.2,75.0,72.9,69.2,65.9,63.5,62.1, 55.3,39.0,38.6；HRMS(ESI)calcd for C55H56N3O12PNa[M+Na]+1004.3494,found 1004.3499.
实施例15化合物Ⅲ-15
将供体Ⅰ-5(30mg,0.042mmol)和相应受体(13.1mg,0.035mmol),溶于2mL干燥甲苯中，以TMSOTf(0.78μL,0.0035mmol)为催化剂，得到化合物Ⅲ-15(30mg,92％,β/α＝10:1)，为白色固体:1H NMR(500MHz,CDCl3)δ7.77(dd,J＝4.6,3.2Hz,4H),7.51–7.44(m,8H),7.37(d,J＝7.1Hz,2H),7.34–7.26(m,14H),7.22(d,J＝6.8Hz,2H),5.57(s,1H),4.91(d,J＝11.4Hz, 1H),4.86(dd,J＝6.1,2.7Hz,1H),4.84–4.79(m,2H),4.67(d,J＝11.4Hz,1H),4.62–4.56(m, 2H),4.53–4.49(m,1H),4.45(d,J＝10.9Hz,1H),4.29(dd,J＝16.2,7.9Hz,2H),4.14(dd,J＝ 11.7,4.2Hz,1H),4.04–3.98(m,1H),3.87–3.82(m,1H),3.75(d,J＝10.3Hz,1H),3.71(dd,J＝ 9.4,3.5Hz,1H),3.66–3.60(m,1H),3.53–3.45(m,3H),3.39(s,3H),3.25–3.19(m,2H),2.26(dd, J＝12.2,4.0Hz,1H),1.60(dd,J＝22.2,11.8Hz,1H)；13CNMR(125MHz,CDCl3)δ165.9,165.9, 138.8,138.3,138.1,137.5,132.4,132.4,132.3,132.2,132.2,132.0,131.5,131.5,131.2,131.1, 129.0,128.9,128.8,128.8,128.8,128.7,128.6,128.5,128.5,128.3,128.3,128.1,127.9,127.9, 127.9,127.8,127.8,127.7,126.1,101.7,101.4,100.2,82.6,79.4,79.4,78.6,77.3,75.5,74.9,73.1, 71.4,69.2,64.4,62.3,55.4,39.3,38.8,36.5；HRMS(ESI)calcd for C55H57O12PNa[M+Na]+963.3480,found 963.3481.
实施例16化合物Ⅲ-16
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(16mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.70μL,0.0038mmol)为催化剂，得到化合物Ⅲ-16(33mg,94％,βonly),为白色固体:[α]D 20＝33.6(c＝0.1in CHCl3)；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.3Hz,2H),8.04–7.94(m,6H),7.81–7.73(m,2H),7.60–7.29(m,23H),7.26–7.20(m,5H),7.16(d,J＝6.3Hz, 2H),5.89(dd,J＝10.7,3.1Hz,1H),5.73(dd,J＝10.7,3.6Hz,1H),5.30(d,J＝3.6Hz,1H),4.82 (d,J＝11.1Hz,1H),4.71(d,J＝11.0Hz,1H),4.63(d,J＝10.7Hz,1H),4.60–4.48(m,2H), 4.46–4.36(m,3H),4.27(d,J＝8.0Hz,1H),4.14(dd,J＝12.0,3.1Hz,1H),4.04–3.99(m,1H), 3.99–3.90(m,1H),3.53–3.47(m,1H),3.47(s,3H),3.27–3.19(m,1H),3.13–3.07(m,1H),3.04(d, J＝9.7Hz,1H),3.03–2.94(m,1H)；13C NMR(125MHz,CDCl3)δ166.4,165.8,165.8,165.6, 165.6,138.0,137.5,133.5,133.2,133.1,132.3,131.9,131.2,131.2,130.7,130.6,129.9,129.8, 129.8,129.5,129.4,129.0,128.9,128.7,128.6,128.5,128.5,128.4,128.3,128.3,128.0,127.8, 127.7,101.8,97.4,82.2,77.2,76.6,75.2,75.1,74.5,72.4,70.0,69.5,67.7,66.2,64.8,62.6,55.4, 38.2,37.7；HRMS(ESI)calcd for C62H58N3O15PNa[M+Na]+1138.3498,found 1138.3498.
实施例17化合物Ⅲ-17
将供体Ⅰ-5(30mg,0.042mmol)和相应受体(17.7mg,0.035mmol),溶于2mL干燥甲苯中，以TMSOTf(0.78μL,0.0035mmol)为催化剂，得到化合物Ⅲ-17(34mg,83％,β/α＝8.5:1)，为白色固体:1H NMR(600MHz,CDCl3)δ8.01(dd,J＝14.4,7.5Hz,4H),7.97–7.91(m,4H),7.80(dd,J＝12.1,7.4Hz,2H),7.57(d,J＝7.5Hz,1H),7.53–7.30(m,21H),7.23(dd,J＝8.8,5.6 Hz,1H),7.19(d,J＝6.8Hz,2H),5.83–5.77(m,1H),5.67(dd,J＝10.6,3.6Hz,1H),5.22(d,J＝ 3.6Hz,1H),4.70(d,J＝10.6Hz,1H),4.61–4.49(m,3H),4.44–4.33(m,5H),4.15(dd,J＝11.8, 3.7Hz,1H),4.07(dd,J＝11.8,1.9Hz,1H),3.88–3.82(m,1H),3.56(dd,J＝14.8,7.1Hz,1H), 3.45(s,3H),3.30–3.24(m,1H),3.01–2.97(m,1H),2.96–2.92(m,1H),2.45–2.39(m,1H),1.56 (dd,J＝22.2,12.1Hz,1H)；13C NMR(151MHz,CDCl3)δ166.4,166.1,165.9,165.8,165.5,138.1, 137.9,133.6,133.3,133.2,132.3,132.3,132.0,131.2,131.1,131.1,131.0,130.9,130.8,130.8, 129.8,129.8,129.5,129.5,129.3,129.0,128.8,128.7,128.6,128.5,128.5,128.5,128.4,128.4, 128.3,128.2,127.7,127.6,127.5,100.3,97.3,78.6,76.9,74.2,72.6,70.9,70.3,69.2,67.9,64.9, 63.4,55.4,38.3,37.9,36.1；HRMS(ESI)calcd for C62H59O15PNa[M+Na]+1097.3484,found1097.3490.
实施例18化合物Ⅲ-18
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(12mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-18(27mg,83％,β/α＝10:1),为白色固体:1H NMR(500MHz,CDCl3)δ7.85–7.77(m,4H),7.56–7.48(m,6H),7.39–7.30(m,13H),7.23(d,J＝6.5Hz,2H),6.00(d,J＝9.6Hz,1H),5.79(dd,J＝9.3,6.3Hz,1H),5.54(s,1H), 5.40–5.33(m,1H),4.93(d,J＝11.0Hz,1H),4.85–4.75(m,4H),4.50(d,J＝10.9Hz,2H),4.42(d, J＝7.8Hz,1H),4.33–4.25(m,2H),4.17(dd,J＝11.8,5.3Hz,1H),3.64–3.55(m,3H),3.42–3.31 (m,3H),2.88–2.78(m,1H),2.69(dd,J＝17.7,5.1Hz,1H),2.46(s,1H),2.39–2.29(m,2H), 2.24–2.17(m,1H),2.07(dd,J＝20.5,12.2Hz,1H),2.00(d,J＝15.9Hz,1H),1.92(dd,J＝13.3, 8.0Hz,1H),1.85–1.80(m,1H),1.69–1.57(m,4H),1.48–1.41(m,2H),1.19(dd,J＝12.0,9.2Hz, 1H),1.12–1.08(m,6H),0.88–0.82(m,6H)；13C NMR(125MHz,CDCl3)δ176.5,169.8,165.8, 165.8,138.4,138.2,137.7,133.0,132.3,132.3,131.6,131.1,131.1,131.0,131.0,129.7,128.8, 128.8,128.7,128.5,128.4,128.4,128.3,128.1,128.1,127.9,127.8,127.8,127.7,127.7,102.0, 84.5,81.8,77.2,76.3,75.6,75.0,74.9,72.7,70.2,67.7,63.9,41.5,38.9,38.4,37.3,36.5,33.3,33.0, 32.8,30.7,27.5,26.8,23.8,22.8,16.2,13.9,11.8；HRMS(ESI)calcd for C65H75O12PNa[M+Na]+1101.4888,found 1101.4894.
实施例19化合物Ⅲ-19
将供体Ⅰ-4(30mg,0.038mmol)和相应受体(12.6mg,0.031mmol),溶于2mL干燥甲苯中，以TMSOTf(0.70μL,0.0038mmol)为催化剂，得到化合物Ⅲ-19(25.4mg,80％,β/α＝11:1),为白色固体:1H NMR(300MHz,CDCl3)δ7.88–7.78(m,4H),7.62–7.52(m,6H), 7.41–7.34(m,8H),7.29–7.25(m,2H),6.04(d,J＝9.7Hz,1H),5.91–5.79(m,1H),5.57(s,1H), 5.43(d,1H),4.94–4.77(m,4H),4.67–4.42(m,2H),4.38–4.19(m,4H),3.65–3.57(m,2H), 3.43–3.34(m,3H),2.95–2.82(m,1H),2.77–2.66(m,1H),2.55–2.26(m,4H),2.23–1.89(m,4H),1.77–1.40(m,9H),1.18–1.10(m,6H),0.95–0.90(m,6H)；13C NMR(125MHz,CDCl3)δ176.5,169.7,165.7,137.8,137.5,133.0,132.4,131.6,131.1,131.0,131.0,130.9,129.7,128.9,128.8, 128.7,128.5,128.5,128.4,128.4,128.2,128.1,127.9,127.9,101.2,82.7,77.2,76.3,75.4,75.1, 73.0,71.3,67.7,66.0,63.5,41.5,38.8,38.3,37.3,37.1,36.6,34.1,33.0,32.7,30.7,29.7,27.5,26.8, 24.1,22.8,16.2,13.9,11.8；HRMS(ESI)calcd for C58H68N3O11PNa[M+Na]+1036.4484,found 1036.4485.
实施例20化合物Ⅲ-20
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(12mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-20(22mg,68％,βonly),为白色固体：[α]D 20＝-30.6(c＝0.1in CHCl3)；1H NMR(500MHz,CDCl3)δ7.75–7.70(m,4H),7.50–7.46(m,3H),7.41–7.28(m,16H),7.18(d,J＝6.3Hz,2H),6.48(s,1H),6.36(s,2H),6.01–5.90(m,2H),4.98(d,J＝11.0Hz,1H),4.92(d,J＝11.8Hz,1H),4.82(d,J＝11.0Hz,1H), 4.77(d,J＝10.8Hz,1H),4.70(dd,J＝13.5,7.6Hz,2H),4.59(dd,J＝8.7,6.4Hz,1H),4.55(d,J ＝3.7Hz,1H),4.44(dd,J＝13.4,9.7Hz,2H),4.22(d,J＝11.8Hz,1H),4.07(dd,J＝11.9,5.3Hz, 1H),3.99–3.93(m,1H),3.88(d,J＝9.4Hz,1H),3.80–3.76(m,1H),3.75(s,3H),3.68(s,6H),3.55 (dd,J＝9.7,3.4Hz,1H),3.38–3.31(m,2H),3.27–3.21(m,1H),2.78–2.68(m,2H),2.06–1.99(m, 1H)；13C NMR(125MHz,CDCl3)δ174.0,165.6,165.5,152.7,147.9,147.5,138.5,138.2,137.8, 137.3,135.3,132.2,131.3,131.1,131.1,131.0,130.9,130.7,128.7,128.7,128.6,128.4,128.4, 128.0,128.0,127.9,127.9,127.7,109.3,108.3,108.0,101.4,99.2,82.5,81.4,80.5,77.4,77.2,75.5, 75.0,74.2,71.7,70.2,63.9,60.7,56.3,45.6,43.8,39.2,38.5,38.0；HRMS(ESI)calcd forC63H61O15PNa[M+Na]+1111.3640,found 1111.3645.
实施例21化合物Ⅲ-21
将供体Ⅰ-2(30mg,0.035mmol)和相应受体(8.2mg,0.029mmol)，溶于2mL干燥甲苯中，以TMSOTf(0.64μL,0.0029mmol)为催化剂，得到化合物Ⅲ-21(21mg,73％,β/α＝10:1),为白色固体：1H NMR(400MHz,CDCl3)δ7.68–7.61(m,4H),7.43–7.33(m,9H),7.22(m,15H),7.09(dd,J＝7.2,2.1Hz,2H),5.47(s,1H),4.82(t,J＝9.2Hz,1H),4.79–4.71(m,3H),4.69(d,J＝ 3.5Hz,1H),4.69(d,J＝3.5Hz,1H),4.65–4.58(m,2H),4.31(d,J＝10.8Hz,1H),4.21–4.14(m, 2H),4.05(dd,J＝12.0,4.1Hz,1H),4.02-3.98(m,1H),3.76–3.66(m,2H),3.57(d,J＝9.5Hz,1H), 3.54–3.49(m,2H),3.40(d,J＝9.2Hz,1H),3.34(s,3H),3.33–3.28(m,2H),3.26(d,J＝7.9Hz, 1H),3.24–3.19(m,1H)；13C NMR(100MHz,CDCl3)δ165.8,165.7,138.2,137.7,137.7,137.3, 132.4,132.3,132.2,132.2,132.1,131.3,131.1,131.1,131.0,131.0,131.0,130.9,130.9,129.0, 128.8,128.7,128.7,128.6,128.5,128.4,128.4,128.3,128.2,128.1,128.0,127.9,127.8,127.7, 127.6,127.6,127.4,126.3,126.1,103.0,101.2,99.9,84.9,81.7,80.6,78.9,77.2,75.4,75.2,75.0, 72.6,72.6,68.9,63.8,62.8,55.3,38.8,38.2；HRMS(ESI)calcd for C55H57O13PNa[M+Na]+ 979.3429,found 979.3416.
Claims (10)
1.一种β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，将糖基给体、糖基受体及新鲜活化的分子筛加入有机溶剂中常温搅拌0.5～1.5h，然后在将反应体系置于相应温度下，加入催化剂反应完全；反应完全后用三乙胺淬灭，经过滤和真空浓缩，柱层析后即得到相应的糖苷；其反应通式如下：
其中，X选自H、N3或OBn；m为1或0；Y为C或C＝O；n为1、2或3；y为1或2。
2.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，所述糖基给体为吡喃型糖类或呋喃型糖类的葡萄糖、半乳糖、甘露糖、叠氮糖或2-去氧糖；糖基给体保护基为苄基、对甲氧基苄基、乙酰基、烯丙基或叔丁基二甲基硅醚的任意一种或两种，优选为苄基；糖基给体离去基团为N-苯基-三氟乙酰亚胺酯、三氯乙酰亚胺酯、硫苷或邻炔基苯甲酸酯，优选为N-苯基-三氟乙酰亚胺酯或三氯乙酰亚胺酯；反应中催化剂为TMSOTf、TBSOTf、TfOH、BF3·Et2O或PPh3AuNTf2中的一种，优选为TMSOTf或TBSOTf；反应溶剂为二氯甲烷、甲苯、三氟甲苯、氯苯、***或乙腈；温度为-78℃～25℃，优选为-25℃～25℃；分子筛为
MS、
MS或
MS。
3.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，所述糖基给体与氧化磷相连的芳香环为苯环、取代苯环或杂环；取代基选自甲基、溴或氯；杂环为吡啶、咪唑、嘧啶或吡咯。
4.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，所述糖基给体氧化磷侧链的安装不局限于6位羟基，同样适用于2-OH、3-OH和4-OH。
5.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，所述糖基给体I和所述糖基受体ROH的摩尔比为(1.2～2)：(1～1.5)。
6.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，所述糖基受体ROH与有机溶剂的摩尔体积比为0.01～0.1mol/L；所述催化剂的摩尔加入量为糖基给体摩尔量的5％～100％。
7.根据权利要求1所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的方法，其特征在于，式Ⅰ所示的糖基给体选自以下任一结构的化合物：
8.一种如式I所示的用于β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的糖基给体，其特征在于，
其中：X选自H、N3或OBn；m为1或0；Y为C或C＝O；n为1、2或3；y为1或2；
所述糖基给体为吡喃型糖类或呋喃型糖类的葡萄糖、半乳糖、甘露糖、叠氮糖或2-去氧糖；糖基给体保护基为苄基、对甲氧基苄基、乙酰基、烯丙基或叔丁基二甲基硅醚的任意一种或两种，优选为苄基；糖基给体离去基团为N-苯基-三氟乙酰亚胺酯、三氯乙酰亚胺酯、硫苷或邻炔基苯甲酸酯，优选为N-苯基-三氟乙酰亚胺酯或三氯乙酰亚胺酯；与氧化磷相连的芳香环为苯环、取代苯环或杂环；取代基选自甲基、溴或氯；杂环为吡啶、咪唑、嘧啶或吡咯；所述糖基给体氧化磷侧链的安装不局限于6位羟基，同样适用于2-OH、3-OH和4-OH。
9.根据权利要求8所述的用于β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的糖基给体，其特征在于，部分糖基给体的合成通式如下：
或者为：
10.权利要求8用于所述β-2-脱氧糖、2-脱氧-2-叠氮糖或葡萄糖苷键立体选择性合成的糖基给体，其特征在于，6-位安装的氧化磷侧链合成通式如下：
具体步骤为：将I-a与I-b溶于DMSO中，然后加入KOH水溶液，然后在40-60℃下反应1-2h，反应完全后，调pH为1-2，析出白色晶体，过滤即得I-c。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163483A (zh) * | 2021-12-14 | 2022-03-11 | 中国药科大学 | 一种高效立体选择性α-糖苷化产物的合成方法 |
| CN115286668A (zh) * | 2022-08-17 | 2022-11-04 | 中国药科大学 | 一种β-2,6-二脱氧糖与鼠李糖苷键立体选择性合成的方法 |
| CN118084414A (zh) * | 2024-04-29 | 2024-05-28 | 湖南固力工程新材料有限责任公司 | 一种超高性能混凝土及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541933A (zh) * | 2016-01-27 | 2016-05-04 | 陕西师范大学 | 一种双三氟甲磺酰亚胺试剂活化糖基化反应提高β-糖苷键立体选择性的方法 |
| CN109912642A (zh) * | 2019-04-10 | 2019-06-21 | 四川轻化工大学 | 一种β-2-脱氧糖苷键的立体选择性合成的方法 |
-
2021
- 2021-03-09 CN CN202110253978.9A patent/CN113527388B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541933A (zh) * | 2016-01-27 | 2016-05-04 | 陕西师范大学 | 一种双三氟甲磺酰亚胺试剂活化糖基化反应提高β-糖苷键立体选择性的方法 |
| CN109912642A (zh) * | 2019-04-10 | 2019-06-21 | 四川轻化工大学 | 一种β-2-脱氧糖苷键的立体选择性合成的方法 |
Non-Patent Citations (2)
| Title |
|---|
| MARTIN D. WITTE,: "Synthesis and Biological Evaluation of a Chitobiose-Based Peptide N-Glycanase Inhibitor Library", J. ORG. CHEM., vol. 74, pages 605 * |
| XU KE等: "Investigation of the remote acyl group participation in glycosylation from conformational perspectives by using trichloroacetimidate as the acetyl surrogate", ORG. CHEM. FRONT.,, vol. 7, no. 13, pages 1606 - 1615 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163483A (zh) * | 2021-12-14 | 2022-03-11 | 中国药科大学 | 一种高效立体选择性α-糖苷化产物的合成方法 |
| CN114163483B (zh) * | 2021-12-14 | 2023-12-01 | 中国药科大学 | 一种立体选择性α-糖苷化产物的合成方法 |
| CN115286668A (zh) * | 2022-08-17 | 2022-11-04 | 中国药科大学 | 一种β-2,6-二脱氧糖与鼠李糖苷键立体选择性合成的方法 |
| CN118084414A (zh) * | 2024-04-29 | 2024-05-28 | 湖南固力工程新材料有限责任公司 | 一种超高性能混凝土及其制备方法 |
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