CN114163483A - 一种高效立体选择性α-糖苷化产物的合成方法 - Google Patents
一种高效立体选择性α-糖苷化产物的合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
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- 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
- C07H15/24—Condensed ring systems having three or more rings
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract
本发明公开了一种高效立体选择性α‑糖苷化合物的合成方法。该方法利用糖基给体上的N‑苯基‑三氟乙酰亚酰胺(PTFAI)的远程参与作用，从而形成具有高度选择性的糖苷键。该方法可以高效地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α构型的葡萄糖苷、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。PTFAI基团能在K2CO3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
本发明属于化学合成技术领域，涉及远程参与作用，具体涉及一种高效立体选择性α-糖苷化产物的合成方法。
背景技术
α构型的葡萄糖、2脱氧糖以及2-脱氧-2-氨基糖广泛存在于自然界，也广泛分布在药物分子，是构成抗生素、肝素、阿卡波糖等药物的重要结构单元，在药物研究中具有重要作用。由于其广泛的分布性和重要的药理活性，高效地选择性合成α构型的葡萄糖、2-脱氧糖以及2-脱氧-2-氨基糖的方法对新药的研发具有重要意义。
众所周知，对于β糖苷键的构建，最常用的方法是依靠邻基参与作用，该作用通常在糖上引入2-OAc，2-OBz等酰基，而α糖苷键的构建，常常依靠异头位效应，即在没有邻基参与等其他因素的影响下，由于糖环自身导致的电子排斥和反键轨道等原因，更倾向于生成热力学稳定的α异构体，但很遗憾的是此方法对糖苷键的控制程度非常有限，α-糖苷键立体选择性差和底物适用性不佳。
发明内容
针对现有的α糖苷键选择性合成方法的不足，本发明提供一种高效立体选择性α-糖苷化合物的合成方法，以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。
一种高效立体选择性α-糖苷化产物的合成方法，将式Ⅰ所示糖基给体、式Ⅱ所示糖基受体溶于反应溶剂，加入新鲜活化的分子筛，将反应体系置于适宜温度下，加入催化剂反应至完全，加入三乙胺淬灭反应，经过滤、真空浓缩和柱层析，即得到式Ⅲ相应的糖苷化产物，其反应通式如下：
其中，式Ⅰ和式Ⅲ中的X为2位C处的取代基，X选自H、N3或OBn，
式Ⅰ和式Ⅲ中的n代表2位处C的个数，n为1或0。
式Ⅰ和式Ⅲ中亚酰胺的Y选自F、Cl或Br，优选为F；
式Ⅰ和式Ⅲ中与亚酰胺的N相连的芳香环Ar为苯环、取代苯环或杂环；优选的，所述取代苯环的取代基选自甲基、溴、氯，所述杂环为吡啶、咪唑、嘧啶或吡咯；
式Ⅱ所示糖基受体为ROH；
式Ⅱ和式Ⅲ中所述R选自以下结构：
进一步的，式Ⅰ和式Ⅲ中为吡喃型糖类(n＝0)或呋喃型糖类(n＝1)的葡萄糖、半乳糖、甘露糖、2-叠氮糖或2-去氧糖(X＝H,N3 or OBn)。
进一步的，式Ⅰ所示和式Ⅲ中的保护基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，优选的，式Ⅰ和式Ⅲ中的保护基PG为苄基；所述保护基PG的数量为1或2；
式Ⅰ所示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，优选为N-苯基-三氟乙酰亚胺酯或三氯乙酰亚胺酯。
进一步的，所述反应溶剂为二氯甲烷、1,2-二氯乙烷、氯苯、甲苯、三氟甲苯、四氢呋喃、叔丁基甲基醚或乙醚中的一种或两种，优选为二氯甲烷或二氯甲烷和乙醚的混合；
所述分子筛为
MS、
MS或
MS；
所述温度为-40℃～25℃，优选为-20℃～25℃；
所述催化剂为TMSOTf、TBSOTf、TfOH、BF3.Et2O或PPh3AuNTf2中的一种或两种，优选为TMSOTf或TBSOTf。
进一步的，N-苯基-三氟乙酰亚酰胺(PTFAI)的远程参与基团，安装不局限于6位羟基，同样适用于2-OH、3-OH和4-OH。
进一步的，式Ⅰ所示糖基给体和式Ⅱ所示糖基受体ROH的摩尔比为(1.2～2)：(1～1.5)。
进一步的，式Ⅱ所示糖基受体ROH与有机溶剂的摩尔体积比为0.01～0.1mol/L。
进一步的，所述催化剂的摩尔加入量为式Ⅰ所示糖基给体摩尔量的5％～100％。
进一步的，式Ⅰ所示的糖基给体选自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。
在一些实施例中，优选的一种高效立体选择性α-糖苷化合物的合成方法中，式Ⅲ所示糖苷化产物包括Ⅲ-1～Ⅲ-14所示部分结构：
进一步的，式Ⅰ所示糖基给体合成路线为：
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，将式(a)所示给体溶于甲醇、二氯甲烷的混合溶液中，向反应体系中加入甲醇钠调pH值为碱性，室温搅拌至TLC显示反应完全得到反应体系；
(2)向反应体系中加入阳离子交换树脂中和至pH值为中性后，经过滤、真空浓缩和柱层析，得到式(b)所示1，6位羟基同时裸露的糖基给体；
(3)上述给体溶于丙酮溶液，加入N-苯基-三氟乙酰氯和无水碳酸钾，置于50℃反应至TLC显示反应完全，经过滤、真空浓缩和柱层析即得式Ⅰ所示糖苷化给体。
另一些实施例中，优化的糖基给体制备的方法包括以下步骤：
(1)室温下，将式(c)所示给体溶于四氢呋喃，向反应体系中加入水、三苯基膦氢溴酸盐，室温搅拌至TLC显示反应完全，经过滤、真空浓缩和柱层析，得到式(d)所示1，6位羟基同时裸露的糖基给体；
(2)上述给体溶于丙酮溶液，加入N-苯基-三氟乙酰氯和无水碳酸钾，置于50℃反应至TLC显示反应完全，经过滤、真空浓缩和柱层析即得式Ⅰ所示糖苷化给体。
本发明合成方法在糖基给体上连接N-苯基-三氟乙酰亚酰胺(PTFAI)，利用PTFAI基团在糖苷化反应过程中的远程参与作用，类似于邻基参与作用形成大位阻的环状屏蔽结构，能够巧妙地屏蔽β面，促进受体偏向于α面的进攻，从而可以获得优秀的α选择性。
相比现有技术，本发明具有如下有益效果：
(1)开发了一种以PTFAI基团为远程参与基团的糖苷化方法，同时可以以该基团作为离去基团，糖基给体的合成过程十分简便。
(2)该方法能高选择性地合成α构型的葡萄糖苷、2-脱氧糖和2-脱氧-2-叠氮糖糖苷，反应条件温和，底物适用范围广。
(3)该方法可以用于寡糖合成过程中对α糖苷键的构建，且PTFAI基团可在温和的条件下脱除。
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。
本发明所述PTFAI是指：N-苯基-三氟乙酰亚酰胺；
本发明所述PG是指：保护基；
本发明所述Le是指：离去基团；
本发明所述OBn是指：苄氧基；
本发明所述Bn是指：苄基；
本发明所述PMB是指：对甲氧基苄基；
本发明所述Ac是指：乙酰基；
本发明所述All是指：烯丙基；
本发明所述TBS是指：叔丁基二甲基硅醚；
本发明所述STol是指：硫苷，CAS号：1384270-00-1；
本发明所述t-bu是指：叔丁氧羰基；
本发明所述Ph是指：苯环；
本发明所述TMSOTf是指：三氟甲磺酸三甲基硅酯，CAS#:27607-77-8；
本发明所述TBSOTf是指：叔丁基二甲硅基三氟甲磺酸酯，CAS#:69739-34-0；
本发明所述TfOH是指：三氟甲磺酸；
本发明所述BF3·Et2O是指：三氟化硼乙醚溶液；
本发明所述PPh3AuNTf2是指：三苯基膦双(三氟甲磺酰亚胺)金；
本发明所述DCM是指：二氯甲烷；
本发明所述Et2O是指：乙醚；
本发明所述DCM是指：二氯甲烷；
本发明所述Et3N是指：三乙胺，CAS#:121-44-8；
本发明所述Me是指：甲基；
本发明所述MeOH是指：甲醇；
本发明所述MeONa是指：甲醇钠；
本发明所述Bz是指：苯甲酰基；
本发明所述acetone是指：丙酮；
本发明所述TLC是指：薄层色谱法；
本发明式Ⅲ中的所有化合物按照下述路线一制备：
将式Ⅰ所示糖基给体(1.2eq,38mM)、式Ⅱ所示糖基受体(1.0eq)溶解到无水二氯甲烷和乙醚的混合溶液中，加入新鲜活化的
MS分子筛，将反应体系置于0℃加入TMSOTf(0.1eq)，继续搅拌，直到TLC显示反应完全，所述TLC展开剂为石油醚：乙酸乙酯体积比为8:1～2:1。加入Et3N淬灭反应后，过滤、真空浓缩，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化产物的制备都是遵从路线一。
实施例1化合物Ⅲ-1
Ⅰ-2：
糖基受体Ⅱ-1：
Ⅲ-1：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(29.4mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL干燥乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-1(57.2mg，85％，α/β>20:1)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ7.29(dd,J＝6.8,2.7Hz,20H),7.24–7.14(m,12H),7.08(t,J＝7.4Hz,1H),6.73(d,J＝7.7Hz,2H),5.61(d,J＝3.6Hz,1H),5.02(d,J＝11.4Hz,1H),4.91(dd,J＝10.9,2.4Hz,2H),4.83(d,J＝11.6Hz,1H),4.79(d,J＝5.9Hz,1H),4.71(d,J＝12.1Hz,1H),4.61(d,J＝3.9Hz,2H),4.56(d,J＝3.5Hz,3H),4.52(s,2H),4.23(d,J＝11.9Hz,1H),4.15–3.97(m,3H),3.96–3.82(m,4H),3.65(d,J＝10.4Hz,1H),3.61–3.51(m,2H),3.49–3.44(m,1H),3.38(s,3H).13C NMR(126MHz,Chloroform-d)δ144.20,139.05,138.55,138.14,138.03,137.99,137.96,128.65,128.47,128.45,128.41,128.37,128.30,128.24,128.20,128.14,127.94,127.92,127.87,127.73,127.71,127.67,127.65,127.54,127.50,127.13,126.84,123.86,119.56,97.80,96.50,81.92,80.09,79.74,77.75,77.23,75.68,75.23,74.51,73.45,73.39,73.36,73.32,73.24,69.70,69.26,69.06,55.18；HRMS(ESI)calcd for C63H64F3NO11Na[M+Na]+1090.4431,found 1090.4324.
实施例2化合物Ⅲ-2
Ⅰ-5：
糖基受体Ⅱ-1：
Ⅲ-2：
将给体Ⅰ-5(60mg,0.082mmol)和相应受体(31.7mg,0.068mmol)溶于1mL干燥二氯甲烷和1mL干燥乙醚的混合溶液中，以TMSOTf(1.24μL)为催化剂，得到化合物Ⅲ-2(56.6mg，83％，αonly)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ7.40–7.26(m,23H),7.25–7.19(m,3H),7.19–7.02(m,2H),6.71(d,J＝7.2Hz,2H),5.69(d,J＝3.8Hz,1H),5.11(d,J＝10.9Hz,1H),4.93–4.80(m,4H),4.75(d,J＝12.1Hz,1H),4.65–4.59(m,2H),4.58–4.49(m,3H),4.20–4.03(m,3H),3.94–3.71(m,5H),3.69–3.54(m,3H),3.39(s,3H),3.30(dd,J＝10.3,3.9Hz,1H).13C NMR(126MHz,Chloroform-d)δ144.02,138.65,137.89,137.85,137.66,137.62,128.66,128.56,128.54,128.51,128.40,128.36,128.19,128.10,128.07,128.01,127.90,127.58,127.48,127.41,123.92,119.46,97.70,97.44,81.85,80.36,80.27,78.08,77.23,75.56,75.28,75.00,73.53,73.51,73.33,69.52,69.48,69.25,63.34,55.31；HRMS(ESI)calcd for C56H57F3N4O10Na[M+Na]+1025.4027,found 1025.3911.
实施例3化合物Ⅲ-3
Ⅰ-3：
糖基受体Ⅱ-1：
Ⅲ-3：
将给体Ⅰ-3(30mg,0.044mmol)和相应受体(16.9mg,0.036mmol)溶于0.5mL干燥二氯甲烷和0.5mL干燥乙醚的混合溶液中，以TMSOTf(0.66μL)为催化剂，得到化合物Ⅲ-3(29.4mg，85％，αonly)，为无色油状物：1H NMR(500MHz,Chloroform-d)δ7.35–7.27(m,24H),7.24–7.22(m,2H),7.16(t,J＝7.3Hz,1H),7.07(t,J＝7.5Hz,1H),6.73(d,J＝7.8Hz,2H),5.39(d,J＝3.5Hz,1H),5.04(d,J＝11.3Hz,1H),4.94(d,J＝11.1Hz,1H),4.72(d,J＝12.0Hz,1H),4.66–4.60(m,3H),4.58–4.54(m,2H),4.53(s,2H),4.48(d,J＝12.0Hz,1H),4.25(s,2H),3.92–3.83(m,3H),3.75–3.70(m,1H),3.67(d,J＝9.0Hz,3H),3.52(dd,J＝9.6,3.5Hz,1H),3.47(t,J＝9.2Hz,1H),3.40(s,3H),2.15–2.07(m,1H),1.55(s,1H)；13CNMR(126MHz,Chloroform-d)δ144.27,138.67,138.50,138.37,138.21,138.04,128.68,128.50,128.48,128.45,128.35,128.16,127.98,127.81,127.68,127.66,127.62,127.54,127.50,123.88,119.58,99.22,97.79,82.05,80.19,78.09,77.23,76.30,75.41,75.08,73.41,73.26,71.67,70.08,69.91,69.47,55.27,35.71；HRMS(ESI)calcd forC56H58F3NO10Na[M+Na]+984.4013,found 984.3894.
实施例4化合物Ⅲ-4
Ⅰ-2：
糖基受体Ⅱ-2：
Ⅲ-4：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(27.1mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-4(57.3mg，88％，α/β>20:1)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ8.03–7.95(m,4H),7.52–7.43(m,2H),7.39–7.27(m,14H),7.25–7.21(m,5H),7.13–7.07(m,3H),6.76–6.72(m,2H),6.12(dd,J＝10.1,8.4Hz,1H),5.26(dd,J＝10.0,3.5Hz,1H),5.20(d,J＝3.5Hz,1H),4.93–4.86(m,2H),4.80–4.70(m,2H),4.52(d,J＝11.2Hz,1H),4.43–4.31(m,4H),4.27(d,J＝12.4Hz,1H),4.01(d,J＝12.3Hz,1H),3.94(t,J＝9.4Hz,1H),3.86(d,J＝10.2Hz,1H),3.75(s,3H),3.53(t,J＝9.5Hz,1H),3.47(s,3H),3.28(dd,J＝9.8,3.4Hz,1H)；13C NMR(126MHz,Chloroform-d)δ169.12,165.93,165.46,144.10,138.55,138.20,137.95,133.36,133.04,129.96,129.93,129.72,129.05,128.70,128.44,128.41,128.36,128.34,128.16,127.85,127.77,127.73,127.67,127.65,123.97,119.51,98.40,97.42,81.13,79.17,77.24,76.73,75.62,75.11,72.59,71.39,70.83,70.75,69.88,55.88,52.80；HRMS(ESI)calcdfor C57H54F3NO14Na[M+Na]+1056.3496,found 1056.3395.
实施例5化合物Ⅲ-5
Ⅰ-5：
糖基受体Ⅱ-2：
Ⅲ-5：
将给体Ⅰ-5(60mg,0.082mmol)和相应受体(29.3mg,0.068mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.24μL)为催化剂，得到化合物Ⅲ-5(56mg，85％，αonly)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ8.06–7.96(m,4H),7.55–7.48(m,2H),7.44–7.26(m,16H),7.09(t,J＝7.5Hz,1H),6.75(d,J＝7.2Hz,2H),6.13–6.00(m,1H),5.22–5.13(m,2H),5.09(d,J＝3.6Hz,1H),4.87(d,J＝11.1Hz,1H),4.82–4.72(m,2H),4.55(d,J＝11.2Hz,1H),4.50–4.30(m,4H),3.93–3.83(m,2H),3.79(s,3H),3.64(t,J＝9.5Hz,1H),3.47(s,3H),3.28(dd,J＝10.2,3.6Hz,1H).13C NMR(126MHz,Chloroform-d)δ168.77,165.89,165.48,143.94,137.69,137.50,133.41,133.07,129.98,129.81,129.53,128.93,128.75,128.56,128.51,128.46,128.26,128.00,127.73,124.06,119.43,99.34,97.39,80.22,77.72,77.42,77.23,75.67,75.21,71.51,70.82,70.36,70.06,63.58,55.95,52.90；HRMS(ESI)calcd for C50H47F3N4O13Na[M+Na]+991.3092,found 991.2975.
实施例6化合物Ⅲ-6
Ⅰ-2：
糖基受体Ⅱ-3：
Ⅲ-6：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(9.85mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-6(40.7mg，85％，α/β>20:1)，为无色油状物：1H NMR(600MHz,Chloroform-d)δ7.36–7.27(m,17H),7.08(t,J＝7.4Hz,1H),6.78(d,J＝7.4Hz,2H),5.04–4.99(m,2H),4.95(d,J＝10.9Hz,1H),4.84(d,J＝10.8Hz,1H),4.75–4.69(m,2H),4.57(d,J＝10.9Hz,1H),4.48–4.34(m,2H),4.22–4.15(m,1H),4.08(t,J＝9.3Hz,1H),3.58–3.52(m,2H),3.40–3.33(m,1H),2.47–2.39(m,1H),2.16–2.08(m,1H),1.65–1.59(m,2H),1.41–1.31(m,2H),1.06(q,J＝11.8Hz,1H),1.00–0.90(m,2H),0.86(t,J＝6.5Hz,6H),0.72(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ144.17,138.65,138.26,138.01,128.70,128.53,128.42,128.32,128.02,127.96,127.92,127.65,127.61,123.96,119.54,98.57,81.80,81.41,80.69,78.24,77.23,75.64,75.30,73.36,68.77,48.81,42.98,34.30,31.75,24.61,23.00,22.13,21.10,16.08；HRMS(ESI)calcd for C45H52F3NO6Na[M+Na]+782.3747,found 782.3638.
实施例7化合物Ⅲ-7
Ⅰ-5：
糖基受体Ⅱ-3：
Ⅲ-7：
将给体Ⅰ-5(60mg,0.082mmol)和相应受体(10.63mg,0.068mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.24μL)为催化剂，得到化合物Ⅲ-7(42mg，89％，αonly)，为无色油状物：1H NMR(500MHz,Chloroform-d)δ7.40–7.34(m,4H),7.33–7.27(m,8H),7.09(t,J＝7.5Hz,1H),6.78(d,J＝7.7Hz,2H),5.00(d,J＝3.7Hz,1H),4.95–4.91(m,2H),4.89(d,J＝10.5Hz,1H),4.58(d,J＝11.0Hz,1H),4.44(d,J＝12.8Hz,1H),4.37(dd,J＝12.0,5.1Hz,1H),4.18(dd,J＝10.7,4.8Hz,1H),4.06–4.01(m,1H),3.61(t,J＝9.5Hz,1H),3.45–3.42(m,1H),3.39(dd,J＝10.6,4.4Hz,1H),2.35(pd,J＝6.9,2.3Hz,1H),2.10(d,J＝11.4Hz,1H),1.65(ddt,J＝10.9,7.1,3.5Hz,2H),1.40–1.25(m,3H),1.06(t,J＝11.7Hz,1H),0.95(d,J＝7.0Hz,3H),0.91–0.85(m,4H),0.80(d,J＝6.9Hz,3H).13C NMR(126MHz,Chloroform-d)δ144.03,137.76,137.59,128.73,128.71,128.62,128.57,128.54,128.51,128.14,128.09,128.06,127.98,127.94,127.86,124.04,119.49,99.09,81.48,80.24,78.70,75.50,75.36,69.11,64.28,48.84,42.80,34.18,31.69,24.90,22.83,22.12,21.27,15.91；HRMS(ESI)calcd for C38H45F3N4O5Na[M+Na]+717.3342,found717.3235.
实施例8化合物Ⅲ-8
Ⅰ-2：
糖基受体Ⅱ-4：
Ⅲ-8：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(25.5mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-8(54mg，85％，α/β>20:1)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ7.37–7.28(m,17H),7.09(t,J＝7.4Hz,1H),6.76(d,J＝7.8Hz,2H),5.99(d,J＝9.7Hz,1H),5.78(dd,J＝9.7,5.9Hz,1H),5.52(t,J＝3.3Hz,1H),5.38(q,J＝3.1Hz,1H),4.98(dd,J＝21.9,10.8Hz,2H),4.86–4.74(m,3H),4.59(dd,J＝11.4,7.9Hz,3H),4.46–4.31(m,2H),4.13(q,J＝4.5Hz,1H),4.02–3.87(m,2H),3.63–3.50(m,2H),2.65(d,J＝4.8Hz,2H),2.47–2.23(m,4H),2.08–1.87(m,3H),1.86–1.63(m,4H),1.54(s,1H),1.45–1.26(m,3H),1.07(dd,J＝7.2,4.1Hz,6H),0.87(td,J＝7.2,3.6Hz,6H).13C NMR(126MHz,Chloroform-d)δ176.48,169.45,143.95,138.47,137.96,137.74,133.06,131.65,129.69,128.73,128.69,128.57,128.49,128.46,128.33,128.21,128.18,128.03,128.01,127.97,127.88,127.78,127.76,124.07,119.47,95.70,81.72,79.87,77.57,77.24,76.53,75.88,75.44,73.66,69.33,68.00,67.77,41.42,37.34,36.59,35.11,34.82,32.93,32.60,30.68,27.48,26.80,24.09,22.81,16.28,13.93,11.73；HRMS(ESI)calcd for C59H68F3NO10Na[M+Na]+1030.4795,found 1030.4681.
实施例9化合物Ⅲ-9
Ⅰ-5：
糖基受体Ⅱ-4：
Ⅲ-9：
将给体Ⅰ-5(60mg,0.082mmol)和相应受体(27.5mg,0.068mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.24μL)为催化剂，得到化合物Ⅲ-9(51.9mg，81％，αonly)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ7.40–7.29(m,12H),7.10(t,J＝7.5Hz,1H),6.76(d,J＝7.2Hz,2H),5.99(d,J＝9.7Hz,1H),5.78(dd,J＝9.6,6.0Hz,1H),5.52(t,J＝3.3Hz,1H),5.39(d,J＝3.2Hz,1H),5.03(d,J＝3.7Hz,1H),4.94(dd,J＝11.0,6.6Hz,3H),4.61–4.37(m,4H),4.27(t,J＝4.4Hz,1H),4.07–3.92(m,2H),3.68–3.60(m,1H),3.41(dd,J＝10.3,3.7Hz,1H),2.77(t,J＝4.3Hz,2H),2.44–2.24(m,4H),2.08–1.89(m,3H),1.85–1.63(m,4H),1.61–1.57(m,1H),1.44–1.31(m,3H),1.11–1.05(m,6H),0.90–0.84(m,6H)；13C NMR(126MHz,Chloroform-d)δ176.49,168.98,143.85,137.52,137.37,133.01,131.60,129.72,128.76,128.65,128.59,128.34,128.19,128.13,128.10,127.93,124.15,119.45,96.66,80.05,78.09,76.46,75.65,75.50,69.90,69.02,67.75,63.09,41.43,37.34,36.56,35.12,34.66,32.94,32.64,30.68,27.47,26.79,24.08,22.82,16.29,13.93,11.73；HRMS(ESI)calcd for C52H61F3N4O9Na[M+Na]+965.4391,found965.4285.
实施例10化合物Ⅲ-10
Ⅰ-2：
糖基受体Ⅱ-5：
Ⅲ-10：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(23.6mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-10(50.4mg，82％，α/β>20:1)，为无色油状物：1H NMR(400MHz,Chloroform-d)δ7.49(dd,J＝7.6,2.1Hz,2H),7.42–7.26(m,20H),7.25–7.17(m,2H),7.15–7.03(m,4H),6.71(d,J＝7.1Hz,2H),5.58(s,1H),5.04(d,J＝10.7Hz,1H),4.94–4.81(m,6H),4.73(dd,J＝11.3,6.8Hz,2H),4.53(d,J＝11.1Hz,1H),4.31(dd,J＝10.0,4.5Hz,2H),4.21–4.09(m,3H),4.04(dd,J＝12.3,3.5Hz,1H),3.89–3.82(m,2H),3.75(t,J＝10.2Hz,1H),3.67–3.58(m,3H),3.46(s,3H)；13CNMR(126MHz,Chloroform-d)δ144.17,138.63,138.35,138.31,138.07,137.38,128.93,128.64,128.57,128.47,128.46,128.37,128.35,128.24,128.08,128.00,127.94,127.85,127.71,127.65,126.00,123.86,119.53,101.30,97.25,94.40,82.67,82.00,79.48,77.67,75.80,75.56,75.16,74.51,73.10,69.07,68.44,62.30,55.03；HRMS(ESI)calcdfor C56H56F3NO11Na[M+Na]+998.3805,found 998.3694.
实施例11化合物Ⅲ-11
Ⅰ-2：
糖基受体Ⅱ-6：
Ⅲ-11：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(31.9mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-11(59.4mg，85％，α/β>20:1)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ8.05(d,J＝7.4Hz,2H),7.96(d,J＝7.3Hz,4H),7.59(t,J＝7.3Hz,1H),7.50–7.44(m,3H),7.41–7.28(m,16H),7.24–7.15(m,6H),7.06(t,J＝7.3Hz,1H),6.63(d,J＝7.8Hz,2H),5.71(dd,J＝11.0,2.8Hz,1H),5.62(dd,J＝10.9,3.5Hz,1H),5.24(d,J＝3.5Hz,1H),5.08(d,J＝10.8Hz,1H),4.98–4.91(m,2H),4.90–4.81(m,2H),4.76–4.68(m,3H),4.53(d,J＝11.1Hz,1H),4.43(d,J＝2.8Hz,1H),4.36(t,J＝6.4Hz,1H),4.28(d,J＝10.1Hz,1H),4.19(t,J＝9.4Hz,1H),3.97(dd,J＝12.3,3.0Hz,1H),3.75(dd,J＝12.3,1.9Hz,1H),3.65(t,J＝9.5Hz,1H),3.56(dd,J＝9.9,3.3Hz,1H),3.42(s,3H).13C NMR(126MHz,Chloroform-d)δ166.16,166.06,165.97,144.09,138.57,138.13,137.80,133.38,133.19,129.88,129.86,129.82,129.67,129.44,129.37,128.57,128.51,128.49,128.47,128.45,128.39,128.35,128.15,128.06,127.93,127.88,127.82,127.69,123.79,119.49,99.96,97.45,81.72,80.17,77.63,77.23,75.79,75.22,74.32,70.41,69.63,69.15,68.46,63.29,55.43；HRMS(ESI)calcd forC63H58F3NO14Na[M+Na]+1132.3809,found 1132.3704.
实施例12化合物Ⅲ-12
Ⅰ-2：
糖基受体Ⅱ-7：
Ⅲ-12：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(16.4mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-12(49mg，90％，α/β>20:1)，为无色油状物：1H NMR(600MHz,Chloroform-d)δ7.37–7.27(m,17H),7.10(t,J＝7.5Hz,1H),6.78(d,J＝7.4Hz,2H),5.90(d,J＝3.6Hz,1H),5.25(d,J＝3.6Hz,1H),5.00(d,J＝10.8Hz,1H),4.94(d,J＝10.8Hz,1H),4.85–4.78(m,2H),4.73(d,J＝11.7Hz,1H),4.62(d,J＝3.7Hz,1H),4.57(d,J＝10.8Hz,1H),4.53–4.47(m,2H),4.42–4.35(m,1H),4.24(d,J＝2.8Hz,1H),4.14(dd,J＝8.2,2.8Hz,1H),4.07(dd,J＝8.8,4.5Hz,1H),4.05–4.03(m,1H),4.02–3.98(m,2H),3.63–3.55(m,2H),1.49(s,3H),1.42(s,3H),1.28(s,3H),1.25(s,3H)；13C NMR(101MHz,Chloroform-d)δ144.13,138.52,138.18,137.77,128.89,128.77,128.62,128.60,128.28,128.26,128.13,127.94,127.92,127.66,124.21,119.63,112.16,109.29,105.33,98.13,83.96,81.52,81.24,81.19,80.19,77.77,75.94,75.70,73.34,72.45,69.72,67.20,27.20,27.00,26.32,25.62；HRMS(ESI)calcd for C47H52F3NO11Na[M+Na]+886.3492,found 886.3376.
实施例13化合物Ⅲ-13
Ⅰ-2：
糖基受体Ⅱ-8：
Ⅲ-13：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(9.6mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-13(40.5mg，85％，αonly)，为无色油状物：1H NMR(300MHz,Chloroform-d)δ7.38–7.27(m,17H),7.08(t,J＝7.4Hz,1H),6.77(d,J＝7.3Hz,2H),5.28(d,J＝3.7Hz,1H),5.02(d,J＝10.7Hz,1H),4.94(d,J＝10.8Hz,1H),4.81(d,J＝10.8Hz,1H),4.71(s,2H),4.56(d,J＝10.8Hz,1H),4.44(d,J＝11.6Hz,1H),4.39–4.29(m,1H),4.25(dd,J＝10.3,5.6Hz,1H),4.08(t,J＝9.2Hz,1H),3.59–3.48(m,2H),2.18–2.12(m,3H),1.86(q,J＝11.4Hz,6H),1.62(d,J＝3.6Hz,5H),1.57(s,1H).13C NMR(126MHz,Chloroform-d)δ144.21,138.83,138.21,138.05,128.69,128.53,128.45,128.42,128.15,127.98,127.92,127.85,127.61,123.93,119.57,89.80,81.96,80.23,78.43,75.67,75.29,74.92,72.95,68.09,42.49,36.27,30.69；HRMS(ESI)calcdfor C45H48F3NO6Na[M+Na]+778.3434,found 778.3320.
实施例14化合物Ⅲ-14
Ⅰ-2：
糖基受体Ⅱ-9：
Ⅲ-14：
将给体Ⅰ-2(60mg,0.076mmol)和相应受体(6.8mg,0.063mmol)溶于1mL干燥二氯甲烷和1mL乙醚的混合溶液中，以TMSOTf(1.15μL)为催化剂，得到化合物Ⅲ-14(38.6mg，86％，αonly)，为无色油状物：1H NMR(400MHz,Chloroform-d)δ7.37–7.26(m,17H),7.08(t,J＝7.5Hz,1H),6.75(d,J＝7.1Hz,2H),6.39(d,J＝3.6Hz,1H),4.97(dd,J＝15.3,10.8Hz,2H),4.84(d,J＝10.8Hz,1H),4.73–4.66(m,2H),4.60(d,J＝10.9Hz,1H),4.41(s,2H),4.05–3.95(m,2H),3.80–3.70(m,4H),2.95–2.86(m,2H)；13C NMR(126MHz,Chloroform-d)δ168.82,143.96,138.29,137.68,137.42,128.72,128.60,128.54,128.50,128.10,128.03,128.00,127.85,124.03,119.48,90.36,81.58,78.92,76.67,75.84,75.52,73.42,71.18,38.69,37.58.；HRMS(ESI)calcd for C38H37ClF3NO7Na[M+Na]+734.2211,found 734.2094.
Claims (10)
1.一种高效立体选择性α-糖苷化合物的合成方法，其特征在于，将式Ⅰ所示糖基给体、糖基受体溶于反应溶剂，加入新鲜活化的分子筛，将反应体系置于适宜温度下，加入催化剂反应至完全，加入三乙胺淬灭反应，经过滤、真空浓缩和柱层析，即得到式Ⅲ相应的糖苷化产物，其反应通式如下：
其中，X选自H、N3或OBn；
Y选自F、Cl或Br，优选为F；
式Ⅰ和式Ⅲ中与亚酰胺的N相连的Ar为苯环、取代苯环或杂环；优选的，所述取代苯环的取代基选自甲基、溴、氯，所述杂环为吡啶、咪唑、嘧啶或吡咯；
式Ⅱ所示糖基受体为ROH；
n为1或0。
2.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，式Ⅰ和式Ⅲ为吡喃型糖类或呋喃型糖类的葡萄糖、半乳糖、甘露糖、2-叠氮糖或2-去氧糖。
3.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，式Ⅰ所示和式Ⅲ中的保护基PG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，优选的，式Ⅰ和式Ⅲ中的保护基PG为苄基；所述保护基PG的数量为1或2；式Ⅰ所示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。
4.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，所述反应溶剂为二氯甲烷、1,2-二氯乙烷、氯苯、甲苯、三氟甲苯、四氢呋喃、叔丁基甲基醚或乙醚中的一种或两种，优选为二氯甲烷或二氯甲烷和乙醚的混合；
所述分子筛为
或
所述温度为-40℃～25℃，优选为-20℃～25℃；
所述催化剂为TMSOTf、TBSOTf、TfOH、BF3·Et2O或PPh3AuNTf2中的一种或两种，优选为TMSOTf或TBSOTf。
5.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，N-苯基-三氟乙酰亚酰胺(PTFAI)的远程参与基团，安装不局限于6位羟基，同样适用于2-OH、3-OH和4-OH。
6.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，式Ⅰ所示糖基给体和式Ⅱ所示糖基受体的摩尔比为(1.2～2)：(1～1.5)。
7.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，式Ⅱ所示糖基受体与有机溶剂的摩尔体积比为0.01～0.1mol/L。
8.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，所述催化剂的摩尔加入量为式Ⅰ所示糖基给体摩尔量的5％～100％。
9.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，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：
10.根据权利要求1所述高效立体选择性α-糖苷化合物的合成方法，其特征在于，式Ⅰ所示糖基给体合成路线为：
或者为：
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