CN113121619B - 有机硫脲催化的酚羟基糖苷化方法 - Google Patents
有机硫脲催化的酚羟基糖苷化方法 Download PDFInfo
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- CN113121619B CN113121619B CN202110421842.4A CN202110421842A CN113121619B CN 113121619 B CN113121619 B CN 113121619B CN 202110421842 A CN202110421842 A CN 202110421842A CN 113121619 B CN113121619 B CN 113121619B
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Abstract
本发明公开一种有机硫脲催化的酚羟基糖苷化方法，包括以下步骤：有机溶剂中，以糖基N‑苯基‑三氟乙酰亚胺酯为给体，以酚类化合物为受体，在Kass试剂催化下，发生糖苷化反应，得到酚糖苷。本发明方法条件温和、反应高效、易操作且选择性高。
Description
技术领域
本发明属于糖化学领域，具体而言，涉及有机硫脲催化的糖苷化反应方法。
背景技术
低聚糖和糖缀合物在一系列生物过程中发挥着重要的作用，同时，它们也被广泛用于新药和疫苗的开发。低聚糖和糖缀合物合成的关键步骤是利用糖苷化方法形成糖苷键。
糖苷化反应就是糖基给体(糖的异头位含有容易离去的基团)与受体(具有亲核性质的底物ROH，RNH2等)通过缩醛键连接起来，形成糖苷键的反应。糖苷化反应的重点和难点就是立体构型的控制和收率。在进行糖苷化反应时，由于受体亲核试剂可以从两个方向进攻给体所形成的氧鎓离子，进而会生成α、β两种构型。我们要想得到立体构型专一的产物，一般会采取相应措施。例如：邻基参与、远程参与、糖环的构象、异头位效应、添加剂、溶剂等进行控制。在进行糖苷化时必须严格无水，否则会造成给体的水解，降低糖苷化的产率。给体和受体的活性，促进剂和溶剂都会影响糖苷化的收率。
酚类糖苷化合物在自然界广泛存在,其中很多分子具有较好的生物活性，由于酚羟基的亲核性较差及酚类化合物易于受到亲核进攻,使得酚类化合物的糖苷化比较困难。以现有的方法而言，立体选择性控制所需糖苷键则需要通过糖苷化给体C-2位酰基保护基的邻基参与等策略去实现，而事实上这对于一些亲核性较差的酚类受体是比较困难的，许多合成应用表明现有方法在受体活性较差的反应中会产生副产物甚至无法得到产物。另外对于一些稀有糖(C-2脱氧糖或C-2,6二脱氧糖)的酚类糖苷键的构建因为失去邻基参与则更加困难。事实上，自然界存在大量这类天然产物，以目前的方法去合成这些关键糖苷键仍比较低效。所以发展一种普适性良好的酚类糖苷键构建的新方法是十分有价值的。
发明内容
本发明要解决的技术问题是，提供温和、高效、易操作、通用的酚羟基糖苷化方法，可在中性催化条件，形成高选择性的酚糖苷键。
为解决上述技术问题，本发明采取的技术方案是：
一种有机硫脲催化的酚羟基糖苷化方法，在有机溶剂中，Kass试剂催化下，将如式I所示的糖苷化给体和如式II所示糖苷化受体进行的糖苷化反应，制得如式III所示的糖苷化产物，
其中，Ar为取代或非取代芳基，Gly为糖环上的一个或多个羟基被保护基保护的糖基，所述催化剂为Kass试剂。
在本发明的一些实施方案中，所述芳基为苯基、萘基、蒽基或黄酮基；所述取代的取代基为I、Br、Cl、F、OH、NH2，取代或非取代的C1-C6烷基、取代或非取代的C1-C6烷氧基、取代或非取代的苯基、取代或非取代的COOR、取代或非取代的(CH2)nCOOR，OR或NHR、NR1R2，其中n为1-6中的整数，R、R1和R2各自独立的为甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基，所述取代为单取代或多取代。
在本发明的一些实施方案中，所述糖苷化反应的温度为20～50℃；所述化合物I、化合物II和Kass催化剂的摩尔比为1-2:1:0.1-0.3。
在本发明的一些实施方案中，所述有机溶剂选自CH3CN、DMF、DCM、DCE和甲苯中的一种或多种。
在本发明的一些实施方案中，所述化合物I在有机溶剂中的浓度为0.1-1M。
在本发明的一些实施方案中，所述糖基选自β-D-葡萄糖基、α-D-葡萄糖基、β-D-半乳糖基、α-D-半乳糖基、β-D-甘露糖基、α-D-甘露糖基、β-D-木糖基、α-D-木糖基、β-D-2-氨基葡萄糖基、α-D-2-氨基葡萄糖基、α-L-鼠李糖基、β-L-鼠李糖基、α-D-核糖基、β-D-核糖基、α-L-核糖基、β-L-核糖基、α-D-阿拉伯糖基、β-D-阿拉伯糖基、α-L-阿拉伯糖基、β-L-阿拉伯糖基、α-L-岩藻糖基、β-L-岩藻糖基、β-D-葡萄糖醛酸基、α-D-葡萄糖醛酸基、β-D-半乳糖醛酸基、或者α-D-半乳糖醛酸基。
在本发明的一些实施方案中，所述保护基选自甲基、苄基、苯甲酰基、TMBz、DMNPA、Pic或Pico。
在本发明的一些实施方案中，所述保护基为苄基或Pico。
在本发明的一些实施方案中，所述糖苷化给体选自以下所示的任一化合物，
在本发明的一些实施方案中，所述ArOH选自以下所示的任一化合物：
有益效果：
本发明原料容易取得，反应条件温和，反应产物收率高，立体选择性好，有利于酚糖苷类化合物的开发利用。
附图说明
图1：糖苷化反应条件筛选
图2：酚羟基糖苷化反应
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件进行。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用实验室操作步骤均为相应领域内广泛使用的常规步骤。
本发明中所用的原料或试剂除特别说明之外，均市售可得。所有的试剂都是商品级的，并按照收到的标准使用。所有的水分敏感反应都是在氩气气氛下进行的。用于糖苷化反应的DCM在使用前经CaH2蒸馏并储存在活化的
分子筛上。反应以薄层色谱法(TLC)监测，用紫外(254nm)检测，必要时，用20％硫酸的乙醇溶液喷洒，或用(NH4)6Mo7O24·4H2O(25g/L)和(NH4)4Ce(SO4)4·2H2O(10g/L)在10％的硫酸(aq.)溶液中在80～150℃下炭化显色。Flash柱层析采用硅胶(40-63μm)。1H和13C核磁共振光谱，采用CDCl3、CD3OD、CD3COCD3或D2O，在Bruker AV 400、Bruker AV 600上记录。化学位移(δ)以ppm表示，以四甲基硅烷为内标(CDCl3中的1H NMR)或其他氘化溶剂的残留信号为内标。耦合常数(J)以Hz表示。所有的13C光谱都是质子解耦的。必要时，使用COSY、HSQC、NOESY、HMBC等实验进一步阐明了结构。通过质子核磁共振信号的积分，分析了异头位产物的比值。
术语的定义和解释
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
Kass试剂如下式所示：
室温：具有本领域公知的含义，一般是指25±2℃。
缩写的含义
本发明中使用的缩略语具有本领域常规含义，例如以下缩略语的含义如下：
糖苷化反应条件的筛选：
如图1所示，本发明以给体化合物1a和受体化合物2a为模型化合物，C1-C10为催化剂，在50℃的乙腈中进行糖苷化反应条件筛选，结果见表1。催化剂的筛选结果表明，双(硫脲)尿素C6和C7的产率略高(反应项7-8)，Kass催化剂C10的产率较好(反应项11，72％)。溶剂的影响筛选结果表明，以甲苯和二氯乙烷为溶剂反应3a的收率分别为87％和81％(反应项12-13)。温度和反应时间的影响结果表明，降低温度(50℃到30℃)和缩短反应时间(36h到16h)导致糖苷化产率下降(52％，反应项14)。以化合物1b为给体，以2a为受体，在Kass催化剂C10的催化下，在30℃下反应16小时，以80％的收率产生二糖3a(反应项16)。令人惊讶的是，在相同的反应条件下，没有硝基取代基的全苄基-1-O-(N-苯基-三氟乙酰基)-D-吡喃葡萄糖苷给体1c比给体1b的产率更高，达到86％。为了进一步了解离去基上的硝基取代基对给体反应性的影响，反应项17中，对给体1b和1c进行了竞争性糖苷化。由1c产生的二糖产物3a的收率为95％，给体1b的回收率为82％而1c几乎完全消耗。结果表明，N-苯基-三氟乙酰亚胺酯给体1c在这种糖苷化条件下反应性更强。
因此，后续反应研究以糖基N-苯基-三氟乙酰亚胺酯为给体，以Kass试剂为催化剂进行。
表1硫脲催化的糖苷化反应条件优化
酚羟基糖苷化反应研究
如图2所示，在本发明所述的条件下，将在C-6位上有Pico基团的葡萄糖给体与4-甲氧基苯酚偶联，以94％的产率得到所需的产物6a，并且具有良好的立体选择性(β/α＝8/1)，而在TfOH催化的条件下，仅以67％的收率获得了产物6a，立体选择性差(β/α＝3/1)。在本发明所述的条件下，用富电子酚(4-甲氧基苯酚)和缺电子酚(对羟基苯甲酸甲酯)对各种具有Pico导向基团的糖基给体进行糖苷化，从而得到具有优异的产率以及良好的立体选择性的产物O-芳基糖苷6b-6g和6i。其中，产物O-芳基β-鼠李糖苷6f-6g产率达到98％和97％，立体选择性分别为β/α＝9.6/1和β/α＝15/1。非常缺电子的苯酚(2,4-二氟苯酚和3,4-二苯甲酸甲酯苯酚)的糖苷化反应的产物6h和6j收率达到82％和100％，同时具有良好的立体选择性(β/α≥10/1)。用特殊的酚类受体(2-碘代苯酚、8-碘-1-萘酚和2'-碘-2,6-二甲基-[1,1'-联苯]-4-酚)将糖基给体糖苷化，以高产率得到所需产物6k-6n(75-100％)同时具有出色的立体选择性(β/α>10/1)。L-酪氨酸-N-Boc-甲酯与半乳糖基给体偶联，以88％的收率得到糖基氨基酸6o，且具有出色的立体选择性(β/α＝15/1)，可用于生物活性糖肽合成。在一般的糖苷化反应中，由于类黄酮酚羟基的反应性极低，难以作为受体。而本发明的方法可以将4'，7-二-O-Bn-芹菜素和3,5,7-三-O-Bn-芹菜酚与带有pico导向基团的糖基给体进行糖苷化反应，分别以92％和81％的产率得到产物6p和产物6q立体，同样具有优秀的立体选择性(分别为β/α＝13/1和β/α>20/1)。而最后鼠李糖给体4e和受体大黄素以及山奈酚(5k及5j)反应得到6r、6s，产率和选择性良好，实际上将6r和6s脱除保护基即为天然产物，这进一步体现这种方法的实用性。
本发明糖苷化的一般实验过程A操作如下：
三氟乙酰亚胺酯给体(1.5-2.0当量)和受体(1.0当量)与甲苯共沸除水(3次)。剩余物溶解在干燥的DCM中(DCM中有0.1M受体)，然后加入Kass催化剂(0.2-0.3当量)。反应混合物在室温下搅拌16-36h，通过薄层色谱分析进行监测。溶剂经真空浓缩，柱层析纯化得到产物。
本发明糖苷化的一般实验过程B操作如下：
三氟乙酰亚胺酯给体(1.0-2.0当量)和受体(1.0当量)与甲苯共蒸发(3次)。残渣溶解于干燥的DCM中(DCM中有0.1M受体)，加入新活化的
MS和Kass催化剂(0.2-0.3当量)。反应混合物在室温或加热下搅拌30-72h，通过薄层色谱分析进行监测。溶剂经真空浓缩，柱层析纯化得到产物。
催化剂的合成
催化剂C1，C2，C3为商业可得，C4[1]，C5[2]，C6[3]，C7[3]，C8[4]，C9[5]，C10[6]为已知化合物，参考对应文献制备。
给体的制备
给体1a[7]，1c[8]为已知化合物，参考对应文献制备。
给体的1b的制备
三氟乙酰亚胺酯给体(PTFAI)制备的一般操作过程：将原料(1当量)溶解于装有丙酮(在丙酮中糖的浓度为0.16M)的圆底烧瓶中，后依次加入Cs2CO3(1.5当量)、N-苯基三氟乙酰亚胺氯(或N-芳基三氟乙酰亚胺氯，1.6当量)。保持反应在0℃或室温下搅拌反应数小时，然后将体系过滤并用DCM洗涤滤渣。将所得滤液收集并在在减压下浓缩，粗产物快速通过层析柱纯化(石油醚/乙酸乙酯，加入Et3N)，得到相应的PTFAI给体。
2,3,4,6-四-O-苄基-D-葡萄糖吡喃基-N-(4-硝基)-苯基-2,2,2-三氟乙酰亚胺基给体1b
在上述PTFAI给体制备的一般操作过程下，原料S1(270mg,0.5mmol)在0℃下反应9小时可以生成1b，含有粗产物的体系在层析柱分离之下(PE/EA＝13/1，加入Et3N)可以得到无色油状1b(299mg,0.395mmol,79％)。1H NMR(400MHz,氘代丙酮)δ8.33(d,J＝9.0Hz,1H),8.21(d,J＝8.7Hz,2H),8.04(d,J＝9.0Hz,1H),7.34(tdd,J＝21.1,14.4,7.0Hz,30H),7.08(d,J＝8.6Hz,2H),5.76(s,1H),5.58(s,0.5H),5.01–4.46(m,12H),4.05–3.48(m,9H).13CNMR(101MHz,氘代丙酮)δ149.6,144.5,139.5,139.0,138.8,138.6,138.5,138.35,128.31,128.27,128.22,128.19,128.14,128.11,127.88,127.87,127.8,127.71,127.68,127.6,127.49,127.45,127.37,127.33,127.32,127.2,124.8,124.7,120.9,120.0,97.9,90.4,84.0,81.6,80.9,78.2,77.3,75.6,75.0,74.9,74.6,74.5,74.4,72.84,72.81,71.9,70.1,69.3,68.5,54.6.HRMS(ESI)Calcd for C34H35O5[M-[OC(CF3)＝NPh]]+523.2479,found523.2464.
2,3,4-三-O-苄基-6-O-(2-亚甲基吡啶)-D-葡萄糖吡喃基-N-苯基-2,2,2-三氟乙酰亚胺基给体4a
在N2保护下将原料S2[9](543mg,1.00mmol)、2-吡啶甲酸(176mg,1.40mmol)、DCC(417mg,2mmol)和DMAP(25mg,0.20mmol)依次加入到装有10ml干燥DCM的圆底烧瓶中，保持该混合体系在室温下搅拌反应2小时。反应完成后，将体系过滤所得固体用DCM洗涤两遍，收集所有滤液。将溶有产物的有机相用饱和NaCl溶液洗涤，然后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物无需纯化直接用于下一步。
将上述所得粗产物溶解在10ml混合溶剂(丙酮:H2O＝9:1,V/V)中，在0℃下将NBS(635mg,3.5mmol)加入到体系中搅拌反应。反应1小时后，TLC板显示原料反应完全，向混合体系中加入饱和Na2S2O3溶液淬灭反应，并加入DCM萃取分液。所得有机相依次用饱和NaHCO3溶液、NaCl溶液洗涤，随后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝1/2)得到糖浆S3(445mg,0.8mmol,80％for 2steps)。
在上述PTFAI给体制备的一般操作过程下，原料S3(445mg,0.8mmol)在室温下反应5小时可以生成4a，含有粗产物的体系在层析柱分离之下(PE/EA＝4/1,加入Et3N)可以得到无色糖浆状4a(535mg,0.736mmol,92％)。1H NMR(400MHz,氘代氯仿)δ8.75(d,J＝4.5Hz,1H),8.01(d,J＝7.8Hz,1H),7.70(t,J＝7.7Hz,1H),7.47–7.44(m,1H),7.41–7.20(m,17H),7.08(t,J＝7.4Hz,1H),6.74(d,J＝7.6Hz,2H),5.73(brs,1H),4.97(d,J＝10.8Hz,1H),4.94–4.75(m,4H),4.72–4.45(m,3H),3.82–3.64(m,4H).13C NMR(100MHz,氘代氯仿)δ164.7,150.2,147.7,143.4,138.2,137.7,137.5,137.0,128.8,128.68,128.65,128.36,128.33,128.26,128.21,128.19,128.01,127.98,127.0,125.4,124.4,119.3,97.1,84.6,80.8,76.0,75.3,75.2,73.9,64.1.HRMS(ESI)Calcd for C33H32NO6[M-[OC(CF3)＝NPh]]+538.2224,found 538.2208.
2,3,6-三-O-苄基-4-O-(2-亚甲基吡啶)-D-葡萄糖吡喃基-N-苯基-2,2,2-三氟乙酰亚胺基给体4b
在N2保护下将原料S4[10](543mg,1.00mmol)、2-吡啶甲酸(176mg,1.40mmol)、DCC(417mg,2mmol)和DMAP(25mg,0.20mmol)依次加入到装有10ml干燥DCM的圆底烧瓶中，保持该混合体系在室温下搅拌反应2小时。反应完成后，将体系过滤所得固体用DCM洗涤两遍，收集所有滤液。将溶有产物的有机相用饱和NaCl溶液洗涤，然后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物无需纯化直接用于下一步。
将上述所得粗产物溶解在10ml混合溶剂(丙酮:H2O＝9:1,V/V)中，在0℃下将NBS(635mg,3.5mmol)加入到体系中搅拌反应。反应1小时后，TLC板显示原料反应完全，向混合体系中加入饱和Na2S2O3溶液淬灭反应，并加入DCM萃取分液。所得有机相依次用饱和NaHCO3溶液、NaCl溶液洗涤，随后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝1/2)得到糖浆S5(440mg,0.79mmol,79％for 2steps)。
在上述PTFAI给体制备的一般操作过程下，原料S5(440mg,0.79mmol)在室温下反应5小时可以生成4b，含有粗产物的体系在层析柱分离之下(PE/EA＝4/1,加入Et3N)可以得到无色糖浆状4b(523mg,0.72mmol,91％)。1H NMR(400MHz,氘代氯仿)δ8.72(d,J＝8.7Hz,1H),7.98(dt,J＝7.9Hz,1H),7.78(td,J＝7.7,1.8Hz,1H),7.45(m,1H),7.40–7.01(m,18H),6.81(d,J＝7.7Hz,2H),5.70(s,1H),5.47(t,J＝9.6Hz,1H),4.90–4.74(m,3H),4.66(d,J＝11.4Hz,1H),4.49(d,J＝1.2Hz,2H),3.86(m,,3H),3.63(m,2H).13C NMR(100MHz,氘代氯仿)δ164.1,149.9,147.5,143.4,137.9,137.8,137.7,137.0,128.9,128.6,128.4,128.3,128.2,128.0,127.8,127.65,127.58,127.2,125.7,124.5,119.4,81.7,80.96,75.48,75.46,74.2,73.6,71.6,68.8.HRMS(ESI)Calcd for C33H32NO6[M-[OC(CF3)＝NPh]]+538.2224,found 538.2217.
2,3,6-三-O-苄基-4-O-(2-亚甲基吡啶)-D-半乳糖吡喃基-N-苯基-2,2,2-三氟乙酰亚胺基给体4c
在N2保护下将原料S6[11](543mg,1.00mmol)、2-吡啶甲酸(176mg,1.40mmol)、DCC(417mg,2mmol)和DMAP(25mg,0.20mmol)依次加入到装有10ml干燥DCM的圆底烧瓶中，保持该混合体系在室温下搅拌反应2小时。反应完成后，将体系过滤所得固体用DCM洗涤两遍，收集所有滤液。将溶有产物的有机相用饱和NaCl溶液洗涤，然后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物无需纯化直接用于下一步。
将上述所得粗产物溶解在10ml混合溶剂(丙酮:H2O＝9:1,V/V)中，在0℃下将NBS(635mg,3.5mmol)加入到体系中搅拌反应。反应1小时后，TLC显示原料反应完全，向混合体系中加入饱和Na2S2O3溶液淬灭反应，并加入DCM萃取分液。所得有机相依次用饱和NaHCO3溶液、NaCl溶液洗涤，随后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化(PE/EA＝1/2)得到糖浆S7(456mg,0.82mmol,82％for 2steps)。
在上述PTFAI给体制备的一般操作过程下，原料S7(456mg,0.82mmol)在室温下反应5小时可以生成4c，含有粗产物的体系在层析柱分离之下(PE/EA＝4/1,加入Et3N)可以得到无色糖浆状4c(566mg,0.779mmol,95％)。1H NMR(400MHz,氘代氯仿)δ8.92–8.74(m,1H),8.07(d,J＝7.8Hz,1H),7.82(td,J＝7.7,1.8Hz,1H),7.48(ddd,J＝7.6,4.7,1.2Hz,1H),7.40–7.13(m,17H),7.09(t,J＝7.5Hz,1H),6.79(d,J＝7.7Hz,2H),5.93(d,J＝3.3Hz,1H),5.74(s,1H),4.89(d,J＝11.4Hz,1H),4.85–4.71(m,2H),4.59(d,J＝11.4Hz,1H),4.51(d,J＝11.7Hz,1H),4.41(d,J＝11.7Hz,1H),3.93(t,J＝8.9Hz,1H),3.85–3.70(m,1H),3.63(t,J＝6.7Hz,2H).13C NMR(100MHz,氘代氯仿)δ163.9,150.3,147.5,143.4,137.8,137.44,137.38,137.0,129.3,128.8,128.5,128.41,128.37,128.33,128.29,128.2,128.06,128.0,127.93,127.88,127.83,127.78,127.1,125.5,124.3,119.3,97.1,79.4,75.7,73.7,73.28,72.3,68.0,67.6.HRMS(ESI)Calcd for C33H32NO6[M-[OC(CF3)＝NPh]]+538.2224,found 538.2216.
2,4-di-O-苄基-3-O-(2-亚甲基吡啶)-L-鼠李糖吡喃基-N-苯基-2,2,2-三氟乙酰亚胺基给体4d
在N2保护下将原料S8[12](437mg,1.00mmol)、2-吡啶甲酸(176mg,1.40mmol)、DCC(417mg,2mmol)和DMAP(25mg,0.20mmol)依次加入到装有10ml干燥DCM的圆底烧瓶中，保持该混合体系在室温下搅拌反应2小时。反应完成后，将体系过滤所得固体用DCM洗涤两遍，收集所有滤液。将溶有产物的有机相用饱和NaCl溶液洗涤，然后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物无需纯化直接用于下一步。
将上述所得粗产物溶解在10ml混合溶剂(丙酮:H2O＝9:1,V/V)中，在0℃下将NBS(635mg,3.5mmol)加入到体系中搅拌反应。反应1小时后，TLC监测显示原料反应完全，向混合体系中加入饱和Na2S2O3溶液淬灭反应，并加入DCM萃取分液。所得有机相依次用饱和NaHCO3溶液、NaCl溶液洗涤，随后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝1/2)得到糖浆S9(382mg,0.85mmol,85％for 2steps)。
在上述PTFAI给体制备的一般操作过程下，原料S9(382mg,0.85mmol)在室温下反应5小时可以生成4d，含有粗产物的体系在层析柱分离之下(PE/EA＝4/1,加入Et3N)可以得到无色糖浆状4d(497mg,0.8mmol,94％)。1H NMR(400MHz,氘代氯仿)δ8.93–8.70(m,1H),8.02(d,J＝7.8Hz,0.7H),7.97(d,J＝7.8Hz,0.3H),7.82(m,1H),7.50(m,1H),7.37–7.16(m,8H),7.15–7.00(m,4H),6.84(brs,2H),6.28(brs,0.7H),5.47(dd,J＝9.2,3.4Hz,0.7H),5.12(s,0.3H),4.92–4.88(m,1H),4.82(d,J＝11.0Hz,0.3H),4.69–4.50(m,1H),4.28(m,1H),4.05(brs,1H),3.94(t,J＝9.8Hz,1H),1.43(d,J＝6.0Hz,3H).13C NMR(100MHz,氘代氯仿)δ164.3,164.2,150.15,150.11,147.8,147.5,143.6,143.4,143.3,143.0,137.90,137.86,137.5,137.1,137.0,128.9,128.8,128.7,128.44,128.41,128.33,128.26,128.08,128.01,127.9,127.2,127.1,125.4,125.3,124.6,119.6,119.4,95.4,78.2,77.9,76.6,75.4,75.3,74.7,74.5,73.8,73.4,72.9,72.8,70.9,18.2,18.0.HRMS(ESI)Calcd for C26H26NO5[M-[OC(CF3)＝NPh]]+432.1805,found 432.1790.
2,3-di-O-苄基-4-O-(2-亚甲基吡啶)-L-鼠李糖吡喃基-N-苯基-2,2,2-三氟乙酰亚胺基给体4e
在N2保护下将原料S10[12](437mg,1.00mmol)、2-吡啶甲酸(176mg,1.40mmol)、DCC(417mg,2mmol)和DMAP(25mg,0.20mmol)依次加入到装有10ml干燥DCM的圆底烧瓶中，保持该混合体系在室温下搅拌反应2小时。反应完成后，将体系过滤所得固体用DCM洗涤两遍，收集所有滤液。将溶有产物的有机相用饱和NaCl溶液洗涤，然后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在柱层析下分离纯化(PE/EA＝3/1)得到糖浆状S11(515mg,0.95mmol,95％)。[α]D 25＝-60.0(c 1.2,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.81(d,J＝4.0Hz,1H),8.14(d,J＝7.8Hz,1H),7.85(td,J＝7.7,1.5Hz,1H),7.55–7.47(m,1H),7.43–7.14(m,15H),5.68–5.60(m,1H),5.54(s,1H),4.77–4.67(m,2H),4.56(d,J＝12.2Hz,1H),4.51–4.41(m,2H),4.07–3.99(m,2H),1.30(d,J＝6.2Hz,3H).13C NMR(100MHz,氘代氯仿)δ164.6,149.9,148.0,137.94,137.89,137.1,134.4,131.4,129.2,128.5,128.3,128.1,127.84,127.77,127.67,127.5,127.1,125.8,86.2,76.4,74.7,72.5,72.0,68.2,17.7.HRMS(ESI)calcd for C32H32NO5S[M+H]+542.1996,found 542.2006.
将上述所得化合物S11(515mg,0.95mmol,95％)溶解在10ml混合溶剂(丙酮:H2O＝9:1,V/V)中，在0℃下将NBS(635mg,3.5mmol)加入到体系中搅拌反应。反应1小时后，TLC监测显示原料反应完全，向混合体系中加入饱和Na2S2O3溶液淬灭反应，并加入DCM萃取分液。所得有机相依次用饱和NaHCO3溶液、NaCl溶液洗涤，随后用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝1/2)得到糖浆S12(372mg,0.83mmol,87％)。
在上述PTFAI给体制备的一般操作过程下，原料S12(372mg,0.83mmol)在室温下反应5小时可以生成4e，含有粗产物的体系在层析柱分离之下(PE/EA＝4/1,加入Et3N)可以得到糖浆状4e(464mg,0.747mmol,90％)。1H NMR(400MHz,氘代氯仿)δ8.84–8.79(m,1H),8.17(d,J＝7.8Hz,1H),7.87(td,J＝7.8,1.7Hz,1H),7.55–7.46(m,1H),7.39–7.07(m,13H),6.75(d,J＝7.3Hz,2H),6.25(bs,1H),5.66(t,J＝9.8Hz,1H),4.81–4.62(m,2H),4.53(s,2H),4.22(dd,J＝9.2,6.2Hz,1H),4.06(dd,J＝9.9,2.8Hz,1H),3.85(s,1H),1.33(d,J＝6.1Hz,3H).13C NMR(101MHz,氘代氯仿)δ164.6,149.9,147.8,143.4,137.8,137.6,137.1,128.8,128.4,128.3,128.2,127.9,127.9,127.8,127.1,125.8,124.4,119.5,95.5,76.1,73.8,73.2,73.0,72.6,69.9,17.7.HRMS(ESI)Calcd for C26H26NO5[M-[OC(CF3)＝NPh]]+432.1805,found 432.1785.
受体的制备
受体2a，5a，5b，5c，5d，5e，5f，5h为商业可得。5i[13]为已知化合物参考相关文献制备。
3,5,7-三-O-苄基-山萘酚受体5j
将已知原料S13[14](253mg,0.54mmol)溶于装有10ml干燥DMF溶剂的圆底烧瓶中，在0℃及N2保护下依次将四丁基碘化铵(41mg,0.11mmol)，MOMCl(49μl,0.65mmol)和DIPEA(0.168ml,0.65mmol)加入到反应体系中，然后将混合体系升至室温并搅拌过夜反应。反应完成后，向体系里面加入DCM稀释，将混合溶液依次用HCl溶液(1M)、饱和NaHCO3溶液、NaCl溶液洗涤。分液所得有机相用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝20/1)得到黄色固体中间体(198mg,0.388mmol,72％)。
取上述所得中间体(101mg,0.198mmol)溶于1ml干燥的DMF中，在0℃及N2保护下依次将碘化钠(6mg,0.0396mmol)、K2CO3(55mg,0.396mmol)、和苄溴(48μl,0.396mmol)加入到反应体系中，然后将混合体系升至室温并搅拌过夜反应。反应完成后，向体系里面加入DCM稀释，将混合溶液依次用HCl溶液(1M)、饱和NaHCO3溶液、NaCl溶液洗涤。所得有机相用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝6/1)得到固体S14(80mg,0.133mmol,67％)。[α]D 25＝-1.9(c 0.45,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.05–7.90(m,2H),7.66–7.54(m,2H),7.51–7.20(m,13H),7.14–6.98(m,2H),6.57(d,J＝2.1Hz,1H),6.46(d,J＝2.1Hz,1H),5.29(s,2H),5.24(s,2H),5.10(s,2H),5.09(s,2H),3.51(s,3H).13C NMR(100MHz,氘代氯仿)δ174.0,162.8,159.9,158.9,158.8,153.6,139.8,137.1,136.5,135.8,130.2,129.0,128.9,128.8,128.6,128.3,128.0,127.78,127.76,126.8,124.5,115.9,110.2,98.2,94.3,94.0,74.1,70.9,70.6,56.3.HRMS(ESI)calcd forC38H33O7[M+H]+601.2221,found 601.2223.
将化合物S14溶于装有1.7ml混合溶剂(DCM:MeOH＝1:1)的圆底烧瓶中，在0℃下将乙酰氯(302μl,4.25mmol)加入到体系中搅拌反应。用TLC监测反应完成后，向体系中加入乙酸乙酯稀释，混合体系依次用饱和NaHCO3溶液、NaCl溶液洗涤。体系分液所得有机相用无水Na2SO4干燥并在真空下减压浓缩得到粗产物，所得粗产物在层析柱纯化下(PE/EA＝7/1)得到淡黄色固体5j(42mg,0.0754mmol,89％)。[α]D 25＝-2.1(c 0.25,丙酮)；1H NMR(400MHz,氘代二甲亚砜)δ10.16(s,1H),7.90(d,J＝8.8Hz,2H),7.64(d,J＝7.4Hz,2H),7.56–7.27(m,13H),6.92(d,J＝2.1Hz,1H),6.88(d,J＝8.8Hz,2H),6.70(d,J＝2.2Hz,1H),5.26(s,2H),5.23(s,2H),5.00(s,2H).13C NMR(100MHz,氘代二甲亚砜)δ172.4,162.6,159.6,159.2,158.2,153.1,138.7,137.1,136.9,136.2,130.0,128.6,128.5,128.32,128.27,128.1,128.0,127.6,127.0,121.0,115.4,109.0,97.9,94.2,72.9,70.1,70.0.HRMS(ESI)calcd for C36H29O6[M+H]+557.1959,found 557.1962.
糖苷化反应所用试剂预处理操作
糖苷化所用给体和受体在反应投料使用前先分别于甲苯减压共沸，真空干燥后备用，所用糖苷化溶剂以CaH2充蒸后再用新活化的
MS干燥3次备用。
条件筛选中糖苷化反应实验操作：
将相应预处理的给体(反应项1-14:给体1a,1.0当量,0.1mmol；反应项15:给体1b,1.0当量,0.05mmol；反应项16:给体1c,1.0当量,0.05mmol；反应项17:给体1b+1c,1.0当量+1.0当量,0.05mmol+0.05mmol)、受体2a(2.0当量对应于反应项1-16,1.0当量对应于反应项17)和有机小分子催化剂(不加或0.1当量C1-C10)加入封管里面，然后在N2双排管系统下抽真空、充N2操作。循环换气三次之后，在N2保护下将干燥的DCM(给体在DCM中浓度为83.3mM)加入到封管中，将封管中的混合体系在相应温度下反应16-36小时。经过TLC监测反应完成后，将封管中的混合体系转入圆底烧瓶中，无需淬灭直接减压浓缩得到粗产物，粗产物通过柱层析分离得到相应产物。
实施例1：有机硫脲催化糖苷化制备化合物6a
在一般实验过程A操作下，原料给体4a(54.6mg,0.075mmol)、受体5a(6.4mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应36小时生成6a，粗产物经过柱层析分离纯化(PE/EA＝2.5/1)得到无色糖浆6a(31mg,0.047mmol,94％,α/β＝1/8)。6a实验数据与前人报道一致。
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实施例2：有机硫脲催化糖苷化制备化合物6b
在一般实验过程A操作下，原料给体4b(54.6mg,0.075mmol)、受体5a(6.4mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应48小时生成6b，粗产物经过柱层析分离纯化(PE/EA＝2.5/1)得到无色糖浆6b(28.1mg,0.0425mmol,94％,α/β>20/1)。6b-αisomer:[α]D 25＝43.1(c 1.4,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.74(d,J＝4.6Hz,1H),8.03(d,J＝7.8Hz,1H),7.79(td,J＝7.7,1.7Hz,1H),7.46(m,1H),7.40–7.03(m,18H),6.88–6.70(m,2H),5.54(dd,J＝10.3,9.4Hz,1H),5.36(d,J＝3.5Hz,1H),4.92(d,J＝11.3Hz,1H),4.82(d,J＝12.0Hz,1H),4.73–4.68(m,2H),4.55–4.21(m,4H),3.81(dd,J＝9.6,3.6Hz,1H),3.77(s,3H),3.67–3.45(m,2H).13C NMR(100MHz,氘代氯仿)δ164.1,155.3,150.9,149.9,147.8,138.5,138.0,137.8,137.0,128.6,128.2,128.2,128.1,128.0,127.8,127.49,127.46,127.0,125.7,118.5,114.6,96.8,79.7,79.3,73.6,73.5,71.8,69.3,68.7,55.7.HRMS(ESI)calcd for C40H40NO8[M+H]+662.2748,found662.2744.
实施例3：有机硫脲催化糖苷化制备化合物6c
在一般实验过程A操作下，原料给体4b(54.6mg,0.075mmol)、受体5b(7.8mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里50℃反应40小时生成6c，粗产物经过柱层析分离纯化(PE/EA＝2/1)得到无色糖浆6c(24mg,0.0348mmol,70％,α/β>20/1)。6c-αisomer:[α]D 25＝65.5(c0.75,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.73(d,J＝4.9Hz,1H),8.10–7.95(m,3H),7.80(td,J＝7.7,1.8Hz,1H),7.47(m,1H),7.37–7.00(m,17H),5.58(t,J＝9.9Hz,1H),5.48(d,J＝3.5Hz,1H),4.93(d,J＝11.3Hz,1H),4.84(d,J＝12.1Hz,1H),4.73(d,J＝11.4Hz,1H),4.66(d,J＝12.1Hz,1H),4.48–4.29(m,3H),4.16(dt,J＝10.3,3.5Hz,1H),3.90(s,3H),3.84(dd,J＝9.6,3.5Hz,1H),3.52(m,2H).13C NMR(100MHz,氘代氯仿)δ166.8,164.1,160.3,149.9,147.6,138.3,137.9,137.6,137.0,131.6,128.6,128.24,128.19,128.17,128.0,127.8,127.6,127.5,127.1,125.7,124.4,116.4,95.5,79.5,79.1,75.6,73.8,73.6,71.4,69.6,68.3,52.1.HRMS(ESI)calcd forC41H40NO9[M+H]+690.2698,found 690.2710.
实施例4：有机硫脲催化糖苷化制备化合物6d
在一般实验过程A操作下，原料给体4c(54.6mg,0.075mmol)、受体5a(6.4mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和2.5ml DCM在封管里30℃反应36小时生成6d，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到无色糖浆6d(30.4mg,0.046mmol,92％,α/β＝1/7)。Theαandβisomer cannot be separated.6d-β:1H NMR(400MHz,氘代氯仿)δ8.81(d,J＝4.6Hz,1H),8.11(d,J＝7.8Hz,1H),7.80(t,J＝7.9Hz,1H),7.51–7.42(m,1H),7.38–7.16(m,15H),7.09–7.05(m,2H),6.81(d,J＝8.8Hz,2H),5.93(d,J＝3.3Hz,1H),4.97(t,J＝9.2Hz,2H),4.85(dd,J＝18.5,11.2Hz,2H),4.61(d,J＝11.4Hz,1H),4.55–4.40(m,2H),3.99–3.92(m,2H),3.76(s,3H),3.67(d,J＝6.3Hz,2H).13C NMR(100MHz,氘代氯仿)δ164.0,155.4,151.6,150.2,147.5,138.4,137.7,137.6,137.1,128.42,128.39,128.36,128.32,128.30,128.2,128.01,127.98,127.80,127.75,127.1,125.7,118.5,114.64,114.62,103.1,79.4,78.8,75.6,73.8,72.7,72.4,68.38,68.35,55.7.HRMS(ESI)calcdfor C40H40NO8[M+H]+662.2748,found 662.2766.
实施例5：有机硫脲催化糖苷化制备化合物6e
在一般实验过程A操作下，原料给体4c(54.6mg,0.075mmol)、受体5b(7.8mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和2.5ml DCM在封管里30℃反应30小时生成6e，粗产物经过柱层析分离纯化(PE/EA＝2.5/1)得到无色糖浆6e(27.2mg,0.0394mmol,79％,α/β＝1/10)。6e-βisomer:[α]D 25＝1.6(c2.3,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.71(brs,1H),8.10(d,J＝7.7Hz,1H),8.00(d,J＝8.4Hz,2H),7.81(t,J＝7.6Hz,1H),7.47(brs,1H),7.42–7.15(m,15H),7.11(d,J＝8.6Hz,2H),5.94(d,J＝3.3Hz,1H),5.14(d,J＝7.7Hz,1H),5.00–4.76(m,3H),4.62(d,J＝11.4Hz,1H),4.57–4.37(m,2H),4.09–3.96(m,2H),3.89(s,3H),3.81(m,1H),3.67(d,J＝6.2Hz,2H).13C NMR(100MHz,氘代氯仿)δ166.7,164.0,160.8,150.3,147.5,138.2,137.54,137.48,137.1,131.7,128.5,128.42,128.38,128.3,128.2,128.0,127.9,127.8,127.1,125.6,124.6,116.2,101.1,79.2,78.5,75.7,73.8,73.1,72.4,68.3,68.2,52.0.HRMS(ESI)calcd for C41H40NO9[M+H]+690.2698,found 690.2721.
实施例6：有机硫脲催化糖苷化制备化合物6f
在一般实验过程A操作下，原料给体4d(46.6mg,0.075mmol)、受体5a(6.4mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应30小时生成6f，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到无色糖浆6f(27.1mg,0.049mmol,98％,α/β＝1/9.6)。6f-βisomer:[α]D 25＝54.0(c 1.4,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.80(brs,1H),7.95(d,J＝7.8Hz,1H),7.80(t,J＝7.6Hz,1H),7.50(m,1H),7.40–7.31(m,2H),7.24–7.15(m,5H),7.06–7.03(m,2H),6.99(d,J＝9.1Hz,2H),6.84(d,J＝9.1Hz,2H),5.17(dd,J＝9.8,3.2Hz,1H),5.09(s,1H),5.03(d,J＝12.3Hz,1H),4.83(dd,J＝13.9,11.7Hz,2H),4.70(d,J＝11.0Hz,1H),4.33(d,J＝3.2Hz,1H),3.94(t,J＝9.5Hz,1H),3.77(s,3H),3.58(m,1H),1.47(d,J＝6.1Hz,3H).13C NMR(100MHz,氘代氯仿)δ164.2,155.3,151.3,150.1,147.6,138.1,138.0,136.9,128.6,128.4,128.1,128.0,127.8,127.6,127.1,125.4,118.2,114.6,100.0,78.4,77.0,75.5,75.4,75.0,72.0,55.7,18.2.HRMS(ESI)calcd for C33H34NO7[M+H]+556.2330,found 556.2320.
实施例7：有机硫脲催化糖苷化制备化合物6g
在一般实验过程A操作下，原料给体4d(46.6mg,0.075mmol)、受体5b(7.8mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应36小时生成6g，粗产物经过柱层析分离纯化(PE/EA＝2.5/1)得到无色糖浆6g(28.3mg,0.0485mmol,97％,α/β＝1/15)。6g-βisomer:[α]D 25＝56.0(c 1.3,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.82(d,J＝4.2Hz,1H),8.01(d,J＝8.8Hz,2H),7.96(d,J＝7.8Hz,1H),7.81(t,J＝7.7Hz,1H),7.59–7.44(m,1H),7.39–7.30(m,2H),7.25–7.14(m,5H),7.11–7.05(m,3H),7.03(d,J＝8.8Hz,2H),5.30(s,1H),5.20(dd,J＝9.8,3.2Hz,1H),5.02(d,J＝12.2Hz,1H),4.93–4.78(m,2H),4.72(d,J＝11.0Hz,1H),4.36(d,J＝3.1Hz,1H),3.97(t,J＝9.5Hz,1H),3.89(s,3H),3.67(m,1H),1.48(d,J＝6.1Hz,3H).13C NMR(100MHz,氘代氯仿)δ166.8,164.2,160.6,150.2,147.6,138.0,137.9,137.0,131.7,128.7,128.4,128.2,128.0,127.9,127.8,127.2,125.4,124.4,115.8,98.1,78.2,75.5,75.2,72.3,52.1,18.2.HRMS(ESI)calcd for C34H34NO8[M+H]+584.2279,found 584.2276.
实施例8：有机硫脲催化糖苷化制备化合物6h
在一般实验过程A操作下，原料给体4d(46.6mg,0.075mmol)、受体5c(6.7mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里40℃反应36小时生成6h，粗产物经过柱层析分离纯化(PE/EA＝2.5/1)得到无色糖浆6h(23mg,0.041mmol,82％,α/β＝1/12)。6h-βisomer:[α]D 25＝56.4(c 1.2,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.82(d,J＝4.5Hz,1H),7.96(d,J＝7.9Hz,1H),7.81(td,J＝7.7,1.8Hz,1H),7.51(ddd,J＝7.6,4.7,1.2Hz,1H),7.38–7.28(m,2H),7.24–6.97(m,8H),6.94–6.73(m,2H),5.15(dd,J＝9.8,3.3Hz,1H),5.12(d,J＝0.8Hz,1H),5.05(d,J＝12.3Hz,1H),4.92–4.79(m,2H),4.70(d,J＝10.9Hz,1H),4.46–4.29(m,1H),3.95(t,J＝9.5Hz,1H),3.62–3.52(m,1H),1.46(d,J＝6.1Hz,3H).13C NMR(101MHz,氘代氯仿)δ164.2,159.3(dd,J＝243.9,10.7Hz),154.4(dd,J＝250.2,11.8Hz),150.1,147.6(dd,J＝10.7,3.6Hz),138.0(d,J＝5.2Hz),137.0,128.8,128.4,128.25,128.16,128.1,127.9,127.7,127.1,125.4,119.5(dd,J＝9.5,1.9Hz),111.0(dd,J＝22.6,3.9Hz),105.3(dd,J＝26.9,22.0Hz),100.5,75.4,75.0,74.8,72.3,18.2.HRMS(ESI)calcd for C32H29F2NNaO6[M+Na]+584.1855,found 584.1854.
实施例9：有机硫脲催化糖苷化制备化合物6i
在一般实验过程A操作下，原料给体4e(46.6mg,0.075mmol)、受体5a(6.4mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应40小时生成6i，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到无色糖浆6i(27.5mg,0.0495mmol,99％,α/β>20/1)。6i-αisomer:[α]D 25＝-27.7(c 1.7,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.78(d,J＝4.6Hz,1H),8.14(d,J＝7.8Hz,1H),7.84(td,J＝7.8,1.8Hz,1H),7.49(ddd,J＝7.6,4.7,1.2Hz,1H),7.43–7.13(m,10H),6.93–6.80(m,4H),5.65(t,J＝9.8Hz,1H),5.43(d,J＝1.9Hz,1H),4.87(d,J＝12.4Hz,1H),4.77(d,J＝12.4Hz,1H),4.71–4.51(m,2H),4.28(dd,J＝9.8,3.1Hz,1H),4.15(m,1H),4.00(t,J＝2.3Hz,1H),3.77(s,3H),1.26(d,J＝6.2Hz,3H).13C NMR(100MHz,氘代氯仿)δ164.7,155.0,150.2,149.9,148.0,138.2,138.2,137.1,128.5,128.3,128.1,127.8,127.61,127.56,127.0,125.7,117.5,114.7,97.3,74.8,74.6,73.3,72.3,67.5,55.7,17.8.HRMS(ESI)calcd for C33H34NO7[M+H]+556.2330,found 556.2324.
实施例10：有机硫脲催化糖苷化制备化合物6j
在一般实验过程A操作下，原料给体4d(46.6mg,0.075mmol)、受体5d(11mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里50℃反应40小时生成6j，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到无色糖浆6j(32mg,0.05mmol,quant,α/β＝1/10)。6j-βisomer:[α]D 25＝61.3(c 1.1,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.81(d,J＝4.3Hz,1H),7.96(d,J＝7.8Hz,1H),7.91–7.74(m,2H),7.51(m,1H),7.33(m,2H),7.25–7.16(m,6H),7.15–7.03(m,4H),5.29(s,1H),5.19(dd,J＝9.7,3.2Hz,1H),5.00(d,J＝12.2Hz,1H),4.91–4.77(m,2H),4.72(d,J＝11.0Hz,1H),4.36(d,J＝3.0Hz,1H),3.96(t,J＝9.5Hz,1H),3.92(s,3H),3.88(s,3H),3.66(m,1H),1.47(d,J＝6.1Hz,3H).13C NMR(100MHz,氘代氯仿)δ168.3,167.0,164.2,159.2,150.2,147.5,138.0,137.8,137.0,135.3,131.5,128.7,128.4,128.2,128.0,127.9,127.8,127.2,125.4,124.7,117.8,116.6,98.3,98.2,78.1,75.4,75.2,72.4,52.94,52.90,52.64,52.59,18.2.HRMS(ESI)calcd for C36H36NO6[M+H]+642.2334,found 642.2333.
实施例11：有机硫脲催化糖苷化制备化合物6k
在一般实验过程A操作下，原料给体4a(54.6mg,0.075mmol)、受体5e(11.2mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里30℃反应36小时生成6k，粗产物经过柱层析分离纯化(PE/EA＝3.5/1)得到无色糖浆6k(28.3mg,0.0374mmol,75％,α/β＝1/10)。6k-βisomer:[α]D 25＝14.8(c 0.9,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.77–8.73(m,1H),7.96(d,J＝7.8Hz,1H),7.87–7.74(m,2H),7.46(ddd,J＝7.6,4.7,1.3Hz,1H),7.40–7.00(m,17H),6.78(td,J＝7.6,1.4Hz,1H),5.57(t,J＝9.8Hz,1H),5.48(d,J＝3.4Hz,1H),4.91(d,J＝11.5Hz,1H),4.83(d,J＝12.1Hz,1H),4.76(d,J＝11.5Hz,1H),4.68(d,J＝12.1Hz,1H),4.57–4.32(m,3H),4.20(dt,J＝10.3,3.5Hz,1H),3.83(dd,J＝9.6,3.4Hz,1H),3.58–4.32(m,2H).13C NMR(100MHz,氘代氯仿)δ164.0,155.8,150.0,147.8,139.6,138.31,138.29,137.7,137.0,129.6,128.5,128.4,128.3,128.24,128.19,127.91,127.89,127.84,127.54,127.49,127.0,125.6,124.2,115.2,96.8,87.3,80.0,78.4,75.3,73.6,73.4,71.3,70.1,68.5.HRMS(ESI)calcd for C39H37INO7[M+H]+758.1609,found 758.1617.
实施例12：有机硫脲催化糖苷化制备化合物6l
在一般实验过程A操作下，原料给体4c(54.6mg,0.075mmol)、受体5f(13.5mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和2.5ml DCM在封管里40℃反应40小时生成6l，粗产物经过柱层析分离纯化(PE/EA＝3.5/1)得到糖浆状6l(35.5mg,0.044mmol,88％,α/β＝1/10)。6l-βisomer:[α]D 25＝46.2(c0.8,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.85(d,J＝4.4Hz,1H),8.30–8.20(m,2H),7.85(t,J＝7.7Hz,1H),7.80(d,J＝8.2Hz,1H),7.56–7.12(m,24H),7.06(t,J＝7.8Hz,1H),6.00(d,J＝3.1Hz,1H),5.49(d,J＝7.6Hz,1H),5.14(d,J＝10.7Hz,1H),5.00–4.90(m,2H),4.62(d,J＝11.1Hz,1H),4.53(t,J＝8.4Hz,1H),4.44(d,J＝11.7Hz,1H),4.36(d,J＝11.6Hz,1H),3.99(t,J＝6.4Hz,1H),3.89(dd,J＝9.4,3.1Hz,1H),3.62(d,J＝6.3Hz,2H).13C NMR(100MHz,氘代氯仿)δ163.8,151.1,150.4,147.5,141.7,138.5,137.51,137.49,137.3,136.4,129.2,128.6,128.5,128.4,128.3,128.2,128.1,128.0,127.8,127.7,127.2,127.1,126.3,126.0,125.7,123.5,110.3,100.7,85.8,80.4,77.8,75.7,73.8,72.8,72.3,68.2,67.8.HRMS(ESI)calcd forC43H39INO7[M+H]+808.1766,found 808.1770.
实施例13：有机硫脲催化糖苷化制备化合物6m
在一般实验过程A操作下，原料给体4e(62.2mg,0.1mmol)、受体5e(11.2mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和1ml DCM在封管里40℃反应40小时生成6m，粗产物经过柱层析分离纯化(PE/EA＝3.5/1)得到白色泡沫6m(30mg,0.046mmol,92％,α/β>20/1)。6m-αisomer:[α]D 25＝-16.0(c 1.8,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.81(dd,J＝4.8,1.6Hz,1H),8.11(d,J＝7.8Hz,1H),7.86(td,J＝7.7,1.6Hz,1H),7.74(dd,J＝7.9,1.6Hz,1H),7.51(ddd,J＝7.7,4.7,1.2Hz,1H),7.46–7.39(m,2H),7.39–7.14(m,9H),7.09(dd,J＝8.3,1.4Hz,1H),6.77(td,J＝7.6,1.4Hz,1H),5.68(t,J＝9.9Hz,1H),5.48(d,J＝2.0Hz,1H),4.89(d,J＝12.3Hz,1H),4.76(d,J＝12.2Hz,1H),4.69(d,J＝12.2Hz,1H),4.61(d,J＝12.2Hz,1H),4.38(dd,J＝9.9,3.0Hz,1H),4.21–4.03(m,2H),1.26(d,J＝6.2Hz,3H).13C NMR(100MHz,氘代氯仿)δ164.5,155.3,149.9,147.8,139.4,138.10,138.08,137.2,129.7,128.5,128.4,128.2,128.1,127.9,127.7,127.1,125.7,124.2,115.4,97.9,87.4,76.5,74.9,74.4,73.5,72.3,68.2,17.8.HRMS(ESI)calcd forC32H31INO6[M+H]+652.1191,found 652.1180.
实施例14：有机硫脲催化糖苷化制备化合物6n
在一般实验过程A操作下，原料给体4c(54.6mg,0.075mmol)、受体5g(16.2mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和2.5ml DCM在封管里40℃反应40小时生成6n，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到糖浆状6n(37.9mg,0.044mmol,88％,α/β＝1/10)。6n-βisomer:[α]D 25＝12.6(c 0.75,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.83(d,J＝4.6Hz,1H),8.13(d,J＝7.8Hz,1H),7.95(dd,J＝8.0,1.2Hz,1H),7.83(td,J＝7.8,1.5Hz,1H),7.50(dd,J＝7.7,4.5Hz,1H),7.44–7.08(m,19H),7.03(td,J＝7.6,1.7Hz,1H),6.91–6.81(m,2H),5.95(d,J＝3.3Hz,1H),5.14(d,J＝7.7Hz,1H),5.01(d,J＝10.9Hz,1H),4.87(dd,J＝17.1,11.2Hz,2H),4.63(d,J＝11.4Hz,1H),4.54(d,J＝11.6Hz,1H),4.44(d,J＝11.6Hz,1H),4.07–3.94(m,2H),3.81(dd,J＝9.6,3.4Hz,1H),3.71(dd,J＝6.3,4.1Hz,2H),1.91(s,3H),1.90(s,3H).13C NMR(100MHz,氘代氯仿)δ164.0,156.6,150.3,147.6,145.8,139.2,138.9,138.5,137.72,137.65,137.4,137.2,130.0,128.65,128.63,128.49,128.45,128.41,128.39,128.3,128.2,128.13,128.07,127.9,127.83,127.77,127.2,125.8,115.64,115.60,101.9,101.3,79.4,79.0,75.6,73.9,73.0,72.4,68.6,68.5,20.7.HRMS(ESI)calcd for C47H45INO7[M+H]+862,2235,found 862.2279.
实施例15：有机硫脲催化糖苷化制备化合物6o
在一般实验过程A操作下，原料给体4c(54.6mg,0.075mmol)、受体5h(15mg,0.05mmol)、Kass催化剂(0.2当量,20mg,0.01mmol)和2.5ml DCM在封管里30℃反应30小时生成6o，粗产物经过柱层析分离纯化(PE/EA＝3/1)得到糖浆状6o(36.6mg,0.044mmol,88％,α/β＝1/10)。6o-βisomer:[α]D 25＝22.7(c 1.0,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.81(d,J＝4.6Hz,1H),8.11(d,J＝7.8Hz,1H),7.82(d,J＝7.7Hz,1H),7.49(dd,J＝7.7,4.6Hz,1H),7.41–7.14(m,16H),7.03(d,J＝1.4Hz,4H),5.94(d,J＝3.3Hz,1H),5.04(d,J＝7.7Hz,1H),4.95(d,J＝10.9Hz,1H),4.85(dd,J＝24.2,11.1Hz,2H),4.61(d,J＝11.4Hz,1H),4.55–4.37(m,2H),4.03–3.94(m,2H),3.78(dd,J＝9.6,3.4Hz,1H),3.75–3.63(m,5H),3.11–2.97(m,2H),1.42(s,9H).13C NMR(100MHz,氘代氯仿)δ172.4,163.9,156.5,155.2,150.2,147.4,138.3,137.65,137.55,137.3,130.5,130.4,128.7,128.5,128.43,128.38,128.34,128.30,128.25,128.21,128.1,127.88,127.86,127.8,127.2,125.7,117.1,102.0,80.1,79.3,78.7,75.6,73.9,72.8,72.4,68.3,54.6,37.6,28.4.HRMS(ESI)calcdfor C48H53N2O11[M+H]+833.3644,found 833.3679.
实施例16：有机硫脲催化糖苷化制备化合物6p
在一般实验过程B操作下，原料给体4d(62.2mg,0.1mmol)、受体5i(22.6mg,0.05mmol)、Kass催化剂(0.3当量,30mg,0.015mmol)、新活化的
MS和1ml DCM在封管里60℃反应60小时生成6p，粗产物经过柱层析分离纯化(PE/EA＝1/1)得到白色泡沫6p(40.5mg,0.046mmol,92％,α/β＝1/13)。6p-βisomer:[α]D 25＝-42.8(c 0.75,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.81(d,J＝4.5Hz,1H),8.07(d,J＝7.7Hz,1H),7.86–7.80(m,3H),7.60–7.30(m,13H),7.29–7.11(m,8H),7.06(d,J＝8.4Hz,2H),6.79(d,J＝2.4Hz,1H),6.68(d,J＝2.4Hz,1H),6.59(s,1H),5.93(dd,J＝9.4,3.4Hz,1H),5.61(d,J＝2.0Hz,1H),5.14(s,4H),4.90(d,J＝11.1Hz,1H),4.85–4.75(m,2H),4.70(d,J＝11.1Hz,1H),4.61(dd,J＝3.4,2.0Hz,1H),4.20–4.07(m,1H),3.97(t,J＝9.4Hz,1H).13C NMR(100MHz,氘代氯仿)δ176.9,164.0,162.5,161.3,161.1,159.5,156.7,149.8,148.0,138.4,138.2,137.1,136.3,135.8,128.9,128.8,128.6,128.4,128.32,128.26,128.0,127.8,127.7,127.6,126.9,125.6,124.1,115.3,111.0,107.6,104.6,98.8,97.5,78.9,75.8,75.0,74.9,73.2,70.6,70.3,69.5,18.2.HRMS(ESI)calcd for C55H47NNaO10[M+Na]+904.3092,found 904.3128.
实施例17：有机硫脲催化糖苷化制备化合物6q
在一般实验过程B操作下，原料给体4c(90.9mg,0.125mmol)、受体5j(28mg,0.05mmol)、Kass催化剂(0.3当量,30mg,0.015mmol)、新活化的
MS和1ml DCM在封管里60℃反应64小时生成6q，粗产物经过柱层析分离纯化(PE/EA＝1.5/1)得到糖浆状6q(44.2mg,0.0404mmol,81％,β/α>20/1)。6q-βisomer:[α]D 25＝-4.4(c 1.4,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.84(d,J＝4.4Hz,1H),8.12(d,J＝7.8Hz,1H),7.97(d,J＝8.8Hz,2H),7.84(t,J＝7.6Hz,1H),7.62(d,J＝7.5Hz,2H),7.56–7.05(m,29H),6.58(d,J＝2.2Hz,1H),6.48(d,J＝2.2Hz,1H),5.97(d,J＝3.3Hz,1H),5.29(s,2H),5.19–5.03(m,6H),4.96(d,J＝10.8Hz,1H),4.88(dd,J＝17.2,11.1Hz,2H),4.63(d,J＝11.5Hz,1H),4.58–4.41(m,2H),4.07–3.98(m,2H),3.83(dd,J＝9.6,3.4Hz,1H),3.69(d,J＝6.3Hz,2H).13C NMR(100MHz,氘代氯仿)δ174.0,163.9,162.8,159.9,158.9,158.7,153.4,150.2,147.3,139.9,138.2,137.6,137.5,137.3,137.0,136.5,135.8,130.3,129.0,128.9,128.7,128.6,128.50,128.47,128.45,128.39,128.26,128.24,128.1,127.92,127.90,127.8,127.7,127.2,126.8,125.7,125.4,116.4,110.2,101.4,98.3,94.0,79.3,78.6,75.8,74.1,73.9,73.0,72.4,70.9,70.6,68.2.HRMS(ESI)calcd for C69H60NO12[M+H]+1094.4110,found 1094.4154.
实施例18：有机硫脲催化糖苷化制备化合物6r
在一般实验过程B操作下，原料给体4e(77.6mg,0.125mmol)、受体5k(23.4mg,0.05mmol)、Kass催化剂(0.3当量,30mg,0.015mmol)、新活化的
MS和1ml DCM在封管里50℃反应72小时生成6r，粗产物经过柱层析分离纯化(PE/EA＝4/1)得到黄色油状6r(37.6mg,0.042mmol,84％,α/β＝8/1)。6r-αisomer:[α]D 25＝-30.4(c 0.8,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.79(d,J＝4.5Hz,1H),8.13(d,J＝7.7Hz,1H),8.00(d,J＝1.7Hz,1H),7.86(t,J＝7.7Hz,1H),7.78(d,J＝2.6Hz,1H),7.54–7.48(m,1H),7.44–7.18(m,12H),7.00(d,J＝2.7Hz,1H),5.74–5.55(m,2H),4.88(d,J＝12.2Hz,1H),4.77(d,J＝12.2Hz,1H),4.61(q,J＝12.1Hz,2H),4.25(dd,J＝9.7,3.1Hz,1H),4.08–3.94(m,2H),2.74–2.69(m,4H),2.49(s,3H),1.89–1.78(m,4H),1.51–1.34(m,8H),1.32–1.20(m,7H),1.01–0.93(m,6H).13C NMR(100MHz,氘代氯仿)δ182.1,179.6,172.3,172.1,164.4,160.2,152.4,150.4,149.9,147.7,145.9,138.0,137.8,137.3,136.1,134.3,131.0,128.6,128.4,128.2,128.1,127.75,127.73,127.2 126.0,125.8,123.5,120.7,117.6,112.4,96.8,74.4,74.2,73.6,72.5,68.4,34.5,34.4,31.6,29.8,24.4,24.3,22.6,21.8,17.8,14.1.HRMS(ESI)calcdfor C53H56NO12[M+H]+898.3797,found 898.3819.
实施例19：有机硫脲催化糖苷化制备化合物6s
在一般实验过程B操作下，原料给体4e(77.6mg,0.125mmol)、受体5j(28mg,0.05mmol)、Kass催化剂(0.3当量,30mg,0.015mmol)、新活化的
MS和1ml DCM在封管里55℃反应72小时生成6s，粗产物经过柱层析分离纯化(PE/EA＝2/1)得到糖浆状6s(40.5mg,0.041mmol,82％,α/β>20/1)。6s-αisomer:[α]D 25＝-34.0(c 1.2,CHCl3)；1H NMR(400MHz,氘代氯仿)δ8.80(d,J＝4.7Hz,1H),8.18(d,J＝7.8Hz,1H),7.95(d,J＝8.9Hz,2H),7.88(td,J＝7.7,1.6Hz,1H),7.63(t,J＝7.3Hz,2H),7.52(m,1H),7.48–7.13(m,24H),7.03(d,J＝9.0Hz,2H),6.59(d,J＝2.2Hz,1H),6.47(d,J＝2.2Hz,1H),5.68(t,J＝9.8Hz,1H),5.60(d,J＝1.9Hz,1H),5.29(s,2H),5.11(s,2H),5.09(s,2H),4.91(d,J＝12.4Hz,1H),4.79(d,J＝12.4Hz,1H),4.75–4.53(m,2H),4.33(dd,J＝9.8,3.0Hz,1H),4.12(m,1H),4.07–3.99(m,1H),1.28(d,J＝6.2Hz,3H).13C NMR(100MHz,氘代氯仿)δ174.0,164.5,162.8,159.88,158.86,157.4,153.4,149.7,147.6,139.8,138.1,138.0,137.5,137.0,136.5,135.7,130.3,129.1,128.9,128.7,128.63,128.57,128.56,128.34,128.26,128.2,128.1,128.0,127.8,127.73,127.66,127.6,127.3,126.7,125.9,124.9,115.8,110.2,98.2,96.4,93.9,74.7,74.3,74.2,73.5,72.5,70.8,70.6,67.8,29.8,17.8.HRMS(ESI)calcd for C62H53NO11[M+H]+988.3691,found 988.3726.
对比例1：TfOH-催化糖苷化反应制备化合物6a
给体4a(43.7mg,0.06mmol)、受体5a(6.4mg,0.05mmol)、新活化的
MS和1ml干燥的DCM依次加入到圆底烧瓶中，在N2保护于室温下搅拌10分钟后，将体系置于-20℃下搅拌并加入TfOH(2.3μl,0.025mmol)。将反应慢慢升温至0℃下继续反应5小时，并加入Et3N淬灭反应。将体系过滤后所得滤液旋干得到粗产物并在层析柱下(PE/EA＝3/1)进一步纯化得到无色油状6a(22.2mg,0.0335mmol,67％,α/β＝1/3)。6a实验数据与前人报道一致。[15]
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在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本请所附权利要求书。
Claims (7)
1.一种有机硫脲催化的酚羟基糖苷化方法，其特征在于，在有机溶剂中，Kass试剂催化下，将如式I所示的糖苷化给体和如式II所示糖苷化受体进行糖苷化反应，制得如式III所示的糖苷化产物，
其中，
ArOH选自以下所示的任一化合物：
Gly为糖环上的一个或多个羟基被保护基保护的糖基，
所述糖基选自β-D-葡萄糖基、α-D-葡萄糖基、β-D-半乳糖基、α-D-半乳糖基、β-D-甘露糖基、α-D-甘露糖基、β-D-木糖基、α-D-木糖基、β-D-2-氨基葡萄糖基、α-D-2-氨基葡萄糖基、α-L-鼠李糖基、β-L-鼠李糖基、α-D-核糖基、β-D-核糖基、α-L-核糖基、β-L-核糖基、α-D-阿拉伯糖基、β-D-阿拉伯糖基、α-L-阿拉伯糖基、β-L-阿拉伯糖基、α-L-岩藻糖基、β-L-岩藻糖基、β-D-葡萄糖醛酸基、α-D-葡萄糖醛酸基、β-D-半乳糖醛酸基、或者α-D-半乳糖醛酸基；
所述Kass试剂为：
2.根据权利要求1所述的糖苷化方法，其特征在于，所述糖苷化反应的温度为20～50℃；所述化合物I、化合物II和Kass催化剂的摩尔比为1-2:1:0.1-0.3。
3.根据权利要求1所述的糖苷化方法，其特征在于，所述有机溶剂选自CH3CN、DMF、DCM、DCE和甲苯中的一种或多种。
4.根据权利要求1所述的糖苷化方法，其特征在于，所述化合物I在有机溶剂中的浓度为0.1-1M。
5.根据权利要求1所述的糖苷化方法，其特征在于，所述保护基选自甲基、苄基、苯甲酰基、TMBz、DMNPA、Pic或Pico。
6.根据权利要求5所述的糖苷化方法，其特征在于，所述保护基为苄基或Pico。
7.根据权利要求1所述的糖苷化方法，其特征在于，所述糖苷化给体选自以下所示的任一化合物，
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