CN114891049A - 基于邻炔基苄醚类糖基供体的高效糖基化方法 - Google Patents

基于邻炔基苄醚类糖基供体的高效糖基化方法 Download PDF

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CN114891049A
CN114891049A CN202210755683.6A CN202210755683A CN114891049A CN 114891049 A CN114891049 A CN 114891049A CN 202210755683 A CN202210755683 A CN 202210755683A CN 114891049 A CN114891049 A CN 114891049A
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冯颖乐
柴永海
张双双
蓝新广
王金财
张琦
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Shaanxi Normal University
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Abstract

本发明公开了一种基于邻炔基苄醚类糖基供体的高效糖基化方法，所述邻炔基苄醚类糖基供体可以在催化剂或促进剂作用下与糖类或者非糖类的亲核试剂反应，高效地生成目标糖苷。本发明的成苷方法与已报道的糖基化方法相比，其中的苷元部分(即离去基团部分)不仅具有较高的稳定性，可以作为糖的端位保护基；同时还可以在多种催化剂的作用下被活化离去，并与各种亲核试剂反应生成糖苷。该成苷方式所能适用的底物范围广，反应高效，还能够方便进行Latent‑active合成，从而实现寡糖的快速制备。

Description

基于邻炔基苄醚类糖基供体的高效糖基化方法
技术领域
本发明属于糖苷合成技术领域，具体涉及一种基于邻炔基苄醚类糖基供体的高效糖基化方法。
背景技术
糖类化合物与蛋白质、DNA、脂质并称四大生命基础物质。生物体内的糖类化合物多以聚糖及糖缀合物(如糖脂、糖蛋白)的形式分布于胞外基质及细胞表面，并介导了生命活动中大量复杂的生物过程，如细胞识别、分化、黏附、信号传导、免疫应答，同时还与很多疾病的产生和发展息息相关。从天然产物中直接分离提取是获取糖类化合物的传统方法，但所得的寡糖结构具有微观不均一性，不利于构效关系的精准化研究。随着糖化学的发展，化学合成已经成为获得结构明确寡糖的强有力手段。糖类化合物无论是聚糖、糖缀合物或糖苷，都是通过糖苷键将各种糖单元或者与其它苷元连接而成。因此，糖苷键的高效及高立体选择性构建是大多数糖苷合成的关键过程，同时也是寡糖合成中的关键性科学问题。
在过去的30～40年里，糖基化方法的研究得到了科研工作者的广泛重视，并且有大量的糖基化方法被报道。尽管如此，目前仅有少数几种糖基化方法为糖化学工作者广泛使用，如Schmidt课题组报道的三氯乙酰亚胺酯法(Angew.Chem.,Int.Ed.1980,19,731-732)，Mukaiyama课题组报道的氟代糖法(Chem.Lett.1981,10,431-432)，俞飚院士课题组报道的N-苯基-三氟乙酰亚胺酯法(Tetrahedron Lett.2001,42,2405-2407)、邻苯炔酸酯法(Tetrahedron Lett.2008,49,3604-3608)等等。这些方法中的离去基团易于引入和活化，且离去基团部分所使用的原料通常便宜易得或者易于制备。最重要的是，这些成苷方法底物适用范围广，且反应高效。然而，这些离去基团的稳定性普遍较差，其中的亚胺酯还难以长时间储存。同时，在引入这些离去基团之前，糖的端位也需要以易于选择性脱除的保护基加以保护。并在需要成苷时，才脱除端位保护基，再引入这些离去基团以进行后续的糖基化。这多次的保护及脱保护无疑会导致糖模块的合成路线进一步延长，不利于寡糖的快速制备。
硫苷法(Angew.Chem.Int.Ed.2009,48,1900–1934)具有易于制备、稳定性高以及易于活化等优点，而广泛地用于糖基化。然而，传统硫苷制备所需的硫醇及硫酚具有很难闻的气味。同时，传统的硫苷需要在化学计量的试剂作用下活化成苷。近几年来，也有一些稳定的醚类糖苷被用于寡糖的构建，如俞飚院士课题组报道的邻炔基苄醚法(Chem.Commun.2015,51,13957-1396)、孙建松教授课题组报道的芳基醚法(J.Am.Chem.Soc.2017,139,12736-12744)等。尽管这类糖苷具有较高的稳定性，但邻炔基苄醚法所需要用的炔胺价格昂贵，而芳基醚法则不易引入，且引入和活化均需要化学计量的试剂。
综上所述，发展一种催化剂便宜易得，离去基团廉价、易于制备和引入、且能作为糖的端位保护基(即能稳定于常规保护及脱保护操作)的高效成苷方法对于寡糖的快速制备有着巨大的促进作用。
发明内容
本发明的目的是提供一种基于邻炔基苄醚类糖基供体的糖基化方法，尤其是在催化条件下能实现糖苷键的高效构建，为寡糖的快速制备提供一种实用方法。
针对上述目的，本发明所采用的糖基化方法为：将式I所示邻炔基苄醚类糖基供体与亲核试剂R'-H溶解于非质子性有机溶剂中，并加入催化剂或促进剂室温反应，得到式II所示糖苷；反应方程式如下：
Figure BDA0003717667460000021
式中PG代表保护基，X为O或S原子，R为对甲氧基苯基或正丁基；X’为O、N或S原子；R’代表亲核试剂的亲电基团，H代表氢原子。
上述糖基化方法中，优选邻炔基苄醚类糖基供体与亲核试剂、催化剂或促进剂的摩尔比为1:1.2～2.0:0.05～2。
上述亲核试剂为糖类的伯醇或仲醇，或者非糖类的伯醇、仲醇或叔醇，或者含硫或含氮类亲核试剂。
上述催化剂优选三氟甲磺酸、三氟甲磺酸酐、三氟甲磺酸铜、三氟甲磺酸汞中任意一种，促进剂优选N-碘代丁二酰亚胺和三氟甲磺酸。
上述保护基为乙酰基、苯甲酰基、新戊酰基、苄基、硅基任意一种或多种糖类保护基团的组合。
上述非质子性有机溶剂为四氢呋喃、乙醚、甲苯、1,2-二氯乙烷、二氯甲烷、乙腈中任意一种。
上述糖基化方法中，进一步优选室温反应的时间为0.5～24小时。
上述邻炔基苄醚类糖基供体的制备方法是：在便宜的路易斯酸(如三氟甲磺酸三甲基硅酯、三氟化硼乙醚)作用下，先将邻碘苄醇或邻碘苄硫醇引入到全乙酰化或苯甲酰化糖的端位，然后直接与炔烃
Figure BDA0003717667460000031
通过Sonagashira偶联反应转化为式I所示邻炔基苄醚类糖基供体，或经过一些列“保护-去保护”操作后与炔烃Sonagashira偶联而成。具体反应过程如下：
Figure BDA0003717667460000032
本发明的有益效果如下：
本发明的邻炔基苄醚类糖基供体可以与糖类或者非糖类的亲核试剂反应，高效地生成目标糖苷。本发明的成苷方法与已报道的糖基化方法相比，其中的苷元部分(即离去基团部分)不仅具有较高的稳定性，可以作为糖的端位保护基；同时还可以在多种催化剂和促进剂的作用下被活化离去，并与各种亲核试剂反应生成糖苷。该成苷方式所能适用的底物范围广，反应高效，还能够方便进行Latent-active合成，从而实现寡糖的快速制备。
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。
实施例1
1、糖基供体的合成
(1)将5g(21.36mmol)邻碘苄醇以15mL无水乙醚溶解，冰浴下冷却5min后，向该溶液中缓慢滴加1.22mL(12.82mmol)PBr3，反应1h后，以甲醇淬灭反应，并将反应液倒入水中用乙醚萃取，合并的有机相以无水MgSO4干燥，过滤、浓缩，最终得到白色粉末，即化合物1粗品。称取2.93g(25.64mmol)硫代醋酸钾并与化合物1粗品混合于反应瓶中，并以43mL甲醇溶解，室温反应30min后，反应液以二氯甲烷稀释，倒入水中分液萃取，有机相以无水MgSO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:80洗脱液)，得到4.05g无色透明油状化合物2，产率为65％。反应方程式如下所示：
Figure BDA0003717667460000041
化合物2的表征数据为：IR(KBr)ν(cm-1)1686,1461,1428,1350,729；1H NMR(400MHz,CDCl3)δ7.79(dd,J＝8.0,1.2Hz,1H),7.43(dd,J＝7.6,1.6Hz,1H),7.25(td,J＝7.6,1.2Hz,1H),6.90(td,J＝7.6,1.6Hz,1H),4.21(s,2H),2.31(s,3H)；13C NMR(100MHz,CDCl3)δ194.24,140.19,139.26,130.30,128.82,128.31,100.34,38.51,30.13；HRMS(ESI)C9H9INaOS[M+Na]+:理论值314.9311,实测值314.9307。
(2)将3.04g(10.41mmol)化合物2以21mL甲醇溶解，室温搅拌下向该溶液中加入0.72g(5.21mmol)K2CO3，反应1h后，将反应液以二氯甲烷稀释并以冰稀盐酸水溶液(1M)洗涤，有机相再以饱和NaHCO3水溶液洗涤、无水MgSO4干燥、过滤、浓缩，得到臭味黄色透明油状液体化合物3。
Figure BDA0003717667460000042
(3)将2.03g(5.21mmol)全乙酰化甘露糖及3.04g(12.16mmol)化合物3混合，并以5.5mL无水二氯甲烷溶解，冰浴冷却下，向该溶液中缓慢滴加2.64mL(20.83mmol)三氟化硼乙醚，加完后恢复室温，反应10h后，将反应液以冰的饱和NaHCO3水溶液中和至中性，用二氯甲烷萃取三次，合并的有机相经无水MgSO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:3洗脱液)，得到2.36g白色粉末状化合物4，产率为78％。
Figure BDA0003717667460000051
化合物4的表征数据为：
Figure BDA0003717667460000052
(c 1.01,CHCl3)；IR(KBr)ν(cm-1)2945,2828,1748,1432,1368,1226；1H NMR(400MHz,CDCl3)δ7.85(d,J＝7.6Hz,1H),7.35-7.26(m,2H),6.96(td,J＝8,1.6Hz,1H),5.32-5.25(m,3H),5.18(s,1H),4.43-4.39(m,1H),4.33(dd,J＝12.0,5.2Hz,1H),4.02(dd,J＝12.4,2.0Hz,1H),3.89(q,J＝13.6Hz,2H),2.14(s,3H),2.11(s,3H),2.04(s,3H),1.96(s,3H)；13C NMR(100MHz,CDCl3)δ170.58,169.78,169.68,169.66,140.03,139.15,130.17,129.22,128.43,100.47,81.48,70.56,69.62,69.11,66.21,62.33,40.04,20.85,20.79,20.66,20.54；HRMS(ESI)C21H25INaO9S[M+Na]+:理论值603.0156,实测值603.0158；m.p.116.8-117.0℃。
(4)称取626.24mg(1.08mmol)化合物4于50mL圆底烧瓶中，加入11mL无水甲醇溶解底物，然后缓慢滴入0.5mL0.32mol/L甲醇钠甲醇溶液，室温条件下反应。待TLC监测反应结束后，用酸性树酯将反应液调至中性，过滤，浓缩得到白色粉末化合物5，直接进行下一步。
Figure BDA0003717667460000053
(5)将3.85g(9.33mmol)反应物5以47mL无水乙腈溶解，室温搅拌下向该溶液中依次加入0.44g(1.86mmol)樟脑磺酸以及5.2mL(8.64mmol)苯甲醛二甲缩醛，室温下搅拌7h后，TLC表明反应完全，直接旋干溶剂，柱色谱分离(V甲醇:V二氯甲烷＝1:80洗脱液)，得到2.65g白色粉末状化合物6，产率为57％。
Figure BDA0003717667460000054
化合物6的表征数据为：
Figure BDA0003717667460000055
(c 0.10,CHCl3)；1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.8Hz,1H),7.39-7.36(m,2H),7.30-7.24(m,2H),7.23(dd,J＝7.6,1.6Hz,1H),6.84(td,J＝7.6,1.6Hz,2H),6.87-6.81(m,1H),5.44(s,1H),5.22-5.07(m,1H),4.14(dd,J＝10.0,4.4Hz,1H),4.01-4.06(m,2H),3.98-3.91(m,2H),3.87-3.85(m,1H),3.80(d,J＝2.4Hz,1H),3.76-3.72(m,2H),2.65(s,2H)；13C NMR(100MHz,CDCl3)δ140.00,139.78,137.09,130.27,129.34,129.06,128.38,128.34,126.27,102.32,100.53,83.66,79.11,71.94,69.19,68.61,63.66,39.89；HRMS(ESI)C20H21INaO5S[M+Na]+:理论值523.0047,实测值523.0036；m.p.143.6-144.3℃。
(6)将2.65g(5.30mmol)化合物6以18mL DMF溶解，0℃下加入0.954g60％的NaH(15.90mmol)和1.90mL(15.90mmol)苄溴，室温反应1h，TLC检测反应完全，加水淬灭，用乙酸乙酯萃取三次并合并有机相，有机相经盐洗、无水Na2SO4干燥、过滤、浓缩，得到化合物7。将所得化合物7置于100mL反应瓶中，加入53mL甲醇，搅拌下加入0.101g(0.53mmol)对甲苯磺酸，将反应瓶转移到50℃油浴下反应1h，待反应完全，用少量三乙胺淬灭，直接旋干溶剂，柱色谱分离(V乙酸乙酯:V石油醚＝1:1洗脱液)，得到2.92g无色透明油状化合物8，产率为93％。
Figure BDA0003717667460000061
化合物8的表征数据为：
Figure BDA0003717667460000062
(c 1.02,CHCl3)；IR(KBr)ν(cm-1)3406,3025,2926,2872,1455,1095,1014,736,698.1H NMR(600MHz,CDCl3)δ7.85(d,J＝7.8Hz,1H),7.32-7.26(m,12H),6.94(t,J＝7.2Hz,1H),5.30(s,1H),4.58(d,J＝12.0Hz,1H),4.49(d,J＝12.0Hz,2H),4.39(d,J＝11.4Hz,1H),4.07(t,J＝9.0Hz,1H),4.01-3.95(m,1H),3.88(d,J＝13.2Hz,1H),3.79-3.84(m,4H),3.64(d,J＝9.0Hz,1H),2.74(s,1H),2.28(s,1H)；13C NMR(100MHz,CDCl3)δ140.04,139.93,137.65,137.63,130.21,129.01,128.55,128.40,128.37,127.98,127.89,127.86,127.84,100.55,81.62,79.96,75.19,72.77,72.19,71.61,67.45,62.79,40.32；HRMS(ESI)C27H29INaO5S[M+Na]+:理论值615.0673,实测值615.0679。
(7)称取1.02g(1.73mmol)化合物8于25mL圆底烧瓶中，加入8mL二氯甲烷和4mL水溶解底物，接着在搅拌条件下加入10μL(0.173mmol)冰醋酸、53.91mg(0.345mmol)2,2,6,6-四甲基哌啶氧化物、1.39g(4.31mmol)二醋酸碘苯，搅拌50min后，TLC监测反应结束，用饱和Na2S2O3水溶液淬灭反应，二氯甲烷萃取三次并合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤、浓缩，得到的粗产品与甲苯共沸除水三次，抽真空换氩气三次后，加入7mL无水DMF，0℃下加入0.715g(5.18mmol)K2CO3、0.32mL(5.18mmol)碘甲烷，将烧瓶转移至室温搅拌，待TLC监测反应结束后，加水淬灭，用乙酸乙酯萃取三次并合并有机相，最后有机相经盐析、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:3洗脱液)，得到0.592g透明糖浆状化合物9，产率为55％。
Figure BDA0003717667460000071
化合物9的表征数据：
Figure BDA0003717667460000072
(c 0.60,CHCl3)；IR(KBr)ν(cm-1)3491,3030,2926,2868,1746,1454,1208,1115,1020,738,699,1H NMR(400MHz,CDCl3)δ7.85(dd,J＝8.0,1.2Hz,1H),7.34-7.27(m,8H),7.25(d,J＝3.2Hz,2H),6.95(td,J＝7.6,1.6Hz,1H),5.35(d,J＝1.7Hz,1H),4.62(d,J＝12.4Hz,1H),4.57(d,J＝12.0Hz,1H),4.54-4.50(m,3H),4.33(td,J＝9.2,2.0Hz,1H),3.89(q,J＝13.2Hz,2H),3.80(s,3H),3.75(dd,J＝3.2,2.0Hz,1H),3.67(dd,J＝9.2,3.2Hz,1H),2.93(d,J＝2.4Hz,1H)；13C NMR(100MHz,CDCl3)δ170.42,139.93,139.72,137.87,137.58,130.29,129.00,128.42,128.32,127.95,127.76,127.72,100.50,82.02,78.75,75.28,72.41,72.38,71.98,68.55,52.57,40.23；13C-GATED(100MHz,CDCl3)82.02,(1JC1,H1＝166.0Hz,C-1)；HRMS(ESI)C28H29INaO6S[M+Na]+:理论值643.0622,实测值643.0626。
(8)向550.5mg(0.89mmol)化合物9加入8mL二氯甲烷中，然后滴加153.3mg(1.065mmol)乙酰丙酸，在0℃冷却条件下，向混合物中加入0.22mL(1.42mmol)N,N-二异丙基碳二亚胺和108.34mg(0.89mmol)N,N-4-二甲氨基吡啶，室温搅拌4h后，用饱和NaHCO3水溶液洗涤两次，用二氯甲烷萃取三次并合并有机相，有机相经去离子水和盐水洗涤、无水MgSO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:3洗脱液)，得到613.5mg黄色糖浆状化合物10，产率为96％。
Figure BDA0003717667460000081
化合物10的表征数据：
Figure BDA0003717667460000082
(c 1.02,CHCl3)；IR(KBr)ν(cm-1)3031,2945,2920,2871,1750,1458,1364,1209,1153,1017,739,698；1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.8Hz,1H),7.44(d,J＝7.2Hz,1H),7.32-7.25(m,12H),6.93(t,J＝7.6Hz,1H),5.54(t,J＝6.4Hz,1H),5.48(d,J＝5.4Hz,1H),4.63(d,J＝12.0Hz,1H),4.55-4.47(m,4H),4.04(d,J＝13.2Hz,1H),3.70(d,J＝13.6Hz,1H),3.80(dd,J＝7.0,2.8Hz,1H),3.69(dd,J＝5.2,2.8Hz,1H),3.63(s,3H),2.71(t,J＝6.4Hz,2H),2.61-2.49(m,2H),2.17(s,3H)；13C NMR(100MHz,CDCl3)δ205.92,171.36,168.22,140.18,139.47,137.37,137.35,130.16,128.65,128.12,128.06,128.04,127.75,127.49,127.46,100.39,77.21,74.60,72.17,72.11,69.44,52.18,40.02,37.47,29.59,27.67；HRMS(ESI)C33H35INaO8S[M+Na]+:理论值741.0990,实测值741.0973。
(9)称取1.23g(1.71mmol)化合物10于100mL圆底烧瓶中，加入0.16g(0.615mmol)三苯基膦、0.22g(0.31mmol)三苯基膦氯化钯、59mg(0.31mmol)CuI，然后加入17mLDMF和17mL二异丙胺溶解底物，接着将反应液冷冻排氧气三次后置烧瓶于室温下滴加0.67mL(5.13mmol)1-己炔，搅拌反应4h后TLC监测反应结束，用饱和NH4Cl水溶液淬灭反应，反应放热并产生灰色沉淀，接着用去离子水洗涤三次除去Cu2+，乙酸乙酯萃取三次合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:2.5洗脱液)，得到1.05g黄色糖浆状化合物11，产率为93％。
Figure BDA0003717667460000083
化合物11的表征数据：
Figure BDA0003717667460000084
(c 0.51,CHCl3)；IR(KBr)ν(cm-1)3030,2953,2926,2864,1746,1451,1362,1207,1150,740.696；1H NMR(400MHz,CDCl3)δ7.42-7.17(m,14H),5.54(t,J＝7.2Hz,1H),5.50(d,J＝4.8Hz,1H),4.64(d,J＝12.4Hz,1H),4.55-4.46(m,4H),4.06(d,J＝13.6Hz,1H),4.01(d,J＝13.6Hz,1H),3.80(dd,J＝7.6,2.8Hz,1H),3.70(t,J＝4.0Hz,1H),3.65(s,3H),2.71(t,J＝6.4Hz,2H),2.62-2.50(m,2H),2.46(t,J＝7.2Hz,2H),2.18(s,3H),1.65-1.58(m,2H),1.54-1.45(m,2H),0.95(t,J＝7.2Hz,3H)；13CNMR(100MHz,CDCl3)δ206.14,171.58,168.54,139.58,137.68,137.65,132.36,129.20,128.26,128.21,127.91,127.67,127.60,127.55,126.99,123.79,96.07,74.96,72.29,72.23,69.71,52.37,49.11,37.73,33.87,33.69,30.74,29.80,27.88,25.57,24.89,22.00,19.25,13.60；HRMS(ESI)C39H44NaO8S[M+Na]+:理论值695.2649,实测值695.2644。
称取559.3mg(0.78mmol)化合物10于50mL圆底烧瓶中，加入73.5mg(0.28mmol)三苯基膦、98.4mg(0.14mmol)三苯基膦氯化钯、27mg(0.14mmol)CuI，之后加入13mL DMF和13mL二异丙胺二异丙胺溶解底物，接着将反应液冷冻排氧气三次后，置烧瓶于室温条件下滴加0.31mL(2.34mmol)4-乙炔基苯甲醚，搅拌4h后TLC监测反应结束，用饱和NH4Cl水溶液淬灭反应，反应放热并产生灰色沉淀，接着用去离子水洗涤三次除去Cu2+，乙酸乙酯萃取三次合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1/2.5洗脱液)，得到507.40mg黄色糖浆状化合物12，产率为90％。
Figure BDA0003717667460000091
化合物12的表征数据：
Figure BDA0003717667460000092
(c 0.99,CHCl3)IR(KBr)ν(cm-1)3031,2953,2920,2842,1750,1602,1510,1452,1362,1248,1151,833,743,698；1H NMR(400MHz,CDCl3)δ7.57-7.51(m,3H),7.44(t,J＝3.6Hz,1H),7.34-7.26(m,13H),6.89(dtJ＝8.8,2.8Hz,2H),5.57-5.55(m,2H),4.63(d,J＝12.0Hz,1H),4.57-4.49(m,4H),4.18(d,J＝13.2,1H),4.14(d,J＝13.2,1H),3.85(s,3H),3.83(t,J＝4.8Hz,1H),3.73(dd,J＝5.2,3.2Hz,1H),3.64(s,3H),2.73(t,J＝6.8Hz,2H),2.64-2.50(m,2H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ206.06,171.49,168.42,159.61,139.61,137.535,137.527,132.95,132.02,129.25,128.89,128.17,128.11,127.95,127.82,127.57,127.50,127.04,123.22,115.15,113.89,94.81,86.04,80.91,77.20,74.80,72.14,72.11,71.56,69.60,55.17,52.27,37.60,33.66,29.70,27.78；HRMS(ESI)C42H42NaO9S[M+Na]+:理论值745.2442,实测值745.2428。
2、糖类受体的糖基化反应
方法A：将43.3mg(0.06mmol)化合物12、18.58mg(0.04mmol)化合物13、2.9mg(0.008mmol)三氟甲磺酸铜的混合物以0.8mL无水二氯甲烷溶解，室温搅拌下反应。待TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后通过柱色谱(V乙酸乙酯:V石油醚＝1:2洗脱液)纯化得到33.96mg黄色油状化合物14，产率为91％。
方法B:称取43.4mg(0.06mmol)化合物12与18.58mg(0.04mmol)化合物13于5mL圆底烧瓶中，与甲苯共沸除水三次，加入磁子，抽真空2h，加入0.8mL无水二氯甲烷溶解底物，然后加入18μL(0.002mmol)三氟甲磺酸，并在室温下搅拌。经TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后通过柱色谱(V乙酸乙酯:V石油醚＝1/2洗脱液)纯化，得到34mg黄色糖浆状化合物14，产率为91％。
Figure BDA0003717667460000101
黄色油状化合物14的表征数据：
Figure BDA0003717667460000102
(c 0.29,CHCl3)；IR(KBr)ν(cm-1)3030,2926,2846,1746,1513,1455,1145,1024,741,701；1H NMR(400MHz,CDCl3)δ7.40-7.17(m,27H),5.48(t,J＝7.6Hz,1H),5.11(d,J＝2.4Hz,1H),4.97(d,J＝10.8Hz,1H),4.85(d,J＝10.8Hz,1H),4.79(d,J＝10.8Hz,1H),4.76(d,J＝12.2Hz,1H),4.71(d,J＝12.4Hz,1H),4.65(dd,J＝12.2,4.4Hz,2H),4.58(d,J＝12.2Hz,1H),4.56-4.49(m,3H),4.22(d,J＝7.2Hz,1H),4.00-3.88(m,2H),3.80(dd,J＝8.0,2.8Hz,1H),3.71(dd,J＝12.0,3.2Hz,2H),3.65(d,J＝3.2Hz,1H),3.59(s,3H),3.48-3.38(m,2H),3.30(s,3H),2.67(t,J＝6.6Hz,2H),2.52-2.48(m,2H),2.13(s,3H)；13C NMR(100MHz,CDCl3)δ206.15,171.60,168.70,138.64,138.18,138.09,138.07,137.76,128.44,128.38,128.31,128.23,128.00,127.96,127.90,127.80,127.73,127.70,127.64,127.53,98.66,97.77,81.99,79.99,77.59,77.20,75.78,75.40,74.91,74.17,73.24,72.82,72.24,69.76,69.43,67.01,55.04,52.42,37.71,29.81,27.87；HRMS(ESI)C47H52NaO14[M+Na]+:理论值955.3875,实测值955.3859。
3、非糖受体的糖基化反应
方法A：称取43.2mg(0.06mmol)化合物11与6.3mg(0.04mmol)化合15于5mL圆底烧瓶中，与甲苯共沸除水三次，加入磁子，抽真空2h，然后加入2.9mg(0.008mmol)三氟甲磺酸铜，并加入0.8mL无水二氯甲烷溶解底物，在室温下搅拌。经TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后通过柱色谱(V乙酸乙酯:V石油醚＝1:3洗脱液)纯化得到22.24mg黄色油状化合物16，产率为89％。
Figure BDA0003717667460000111
方法B:称取43.37mg(0.06mmol)化合物12与6.25mg(0.04mmol)化合物15于5mL圆底烧瓶中，与甲苯共沸除水三次，加入磁子，抽真空2h，加入0.8mL无水二氯甲烷溶解底物，然后加入18μL(0.002mmol)三氟甲磺酸，并在室温下搅拌。经TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后通过柱色谱(V乙酸乙酯:V石油醚＝1/3洗脱液)纯化得到21.24mg黄色油状化合物16，产率为85％。
Figure BDA0003717667460000112
黄色油状化合物16的结构表征数据：
Figure BDA0003717667460000113
(c 0.30,CHCl3)；IR(KBr)ν(cm-1)3030,2953,2922,2868,1751,1455,1364,1133,1033,740,698；1H NMR(400MHz,CDCl3)δ7.29-7.21(m,10H),5.45(t,J＝7.6Hz,1H),5.02(s,1H),4.62(t,J＝12.8Hz,2H),4.56(d,J＝12.0Hz,1H),4.52(d,J＝12.0Hz,1H),4.29(d,J＝7.2Hz,1H),3.80(dd,J＝8.0,3.2Hz,1H),3.61(s,3H),3.57(t,J＝3.2Hz,1H),3.31(td,J＝10.4,3.6Hz,1H),2.67(t,J＝6.6Hz,2H),2.58-2.46(m,2H),2.13(s,3H),1.59-1.51(m,4H),1.33-1.29(m,1H),1.21-1.11(m,2H),1.00-0.93(m,1H),0.88(dd,J＝12.8,2.8Hz,1H),0.83(d,J＝6.4Hz,3H),0.78(d,J＝6.8Hz,3H),0.61(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ206.23,171.70,168.98,138.14,138.04,128.28,128.26,127.94,127.64,127.62,127.60,99.91,81.66,77.20,75.95,74.47,72.77,72.64,69.76,52.46,48.67,42.86,37.81,34.23,31.60,29.86,27.94,25.41,23.04,22.20,21.05,16.04；HRMS(ESI)C36H48NaO9[M+Na]+:理论值647.3191,实测值647.3193。
实施例2
1、糖基供体的合成
(1)将3.50g(5.0mmol)全苯甲酰化甘露糖及2.8g(11.2mmol)化合物3混合，并以5mL无水二氯甲烷溶解，冰浴冷却下，向该溶液中缓慢滴加2.5mL(20.25mmol)三氟化硼乙醚，加完后恢复室温反应，反应10h后，将反应液以冰的饱和NaHCO3水溶液中和至中性，用二氯甲烷萃取三次，合并的有机相经无水MgSO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1:3洗脱液)，得到3.43g化合物17，产率为83％。
Figure BDA0003717667460000121
(2)称取2.07g(2.5mmol)化合物17于100mL圆底烧瓶中，加入233mg(0.89mmol)三苯基膦、321mg(0.45mmol)三苯基膦氯化钯、86mg(0.45mmol)CuI，然后加入25mLDMF和25mL二异丙胺溶解底物，接着将反应液冷冻排氧气三次后置烧瓶于室温下滴加0.98mL(7.49mmol)1-己炔，搅拌反应4h后TLC监测反应结束，用饱和NH4Cl水溶液淬灭反应，反应放热并产生灰色沉淀，接着用去离子水洗涤三次除去Cu2+，乙酸乙酯萃取三次合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1/3洗脱液)，得到1.85g化合物18，产率为89％。
Figure BDA0003717667460000131
化合物18的表征数据如下：1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.4Hz,2H,Ar-H),8.03(d,J＝7.4Hz,2H,Ar-H),7.97–7.92(m,2H,Ar-H),7.84–7.78(m,2H,Ar-H),7.61–7.49(m,6H,Ar-H),7.44–7.34(m,10H,Ar-H),7.29–7.27(m,1H,Ar-H),7.24(d,J＝7.8Hz,1H,Ar-H),6.82(d,J＝8.8Hz,2H,Ar-H),6.15(t,J＝10.0Hz,1H,H-4),5.85(dd,J＝10.0,3.2Hz,1H,H-3),5.81(dd,J＝3.2,1.2Hz,1H,H-2),5.60(s,1H,H-2),4.81(dt,J＝10.0,3.2Hz,1H,H-5),4.55(dd,J＝12.4,2.4Hz,1H,H-6a),4.39(dd,J＝12.4,4.0Hz,1H,H-6b),4.19–4.10(m,2H,-CH2Ph),3.76(s,3H,-OCH3)；13C NMR(100MHz,CDCl3)δ166.19,165.48,165.45,165.20,159.87,138.95,133.55,133.52,133.28,133.15,132.56,129.95,129.93,129.82,129.51,129.42,129.01,128.64,128.55,128.54,128.38,128.31,127.91,127.61,123.50,115.15,114.17,86.03,82.34,71.69,70.76,69.30,67.12,62.83,55.35,34.11。
2、糖类受体的糖基化反应
称取43mg(0.052mmol)化合物18与20mg(0.04mmol)化合物19于5mL圆底烧瓶中，与甲苯共沸除水三次，加入磁子，抽真空2h，加入0.8mL无水二氯甲烷溶解底物，然后加入18μL三氟甲磺酸酐，在室温下搅拌。经TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后通过柱色谱(V乙酸乙酯:V石油醚＝1/4洗脱液)纯化，得到42mg化合物20，产率为100％。
Figure BDA0003717667460000132
化合物20的表征数据为:1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.2Hz,2H),7.97–7.88(m,4H),7.79(d,J＝7.2Hz,2H),7.62–7.53(m,2H),7.53–7.47(m,1H),7.45–7.17(m,21H),7.16–7.09(m,1H),7.06–6.98(m,2H),6.99–6.92(m,1H),6.03(t,J＝10.1Hz,1H),5.86(dd,J＝10.2,3.1Hz,1H),5.75–5.70(m,1H),5.61(d,J＝1.6Hz,1H),5.06(d,J＝11.0Hz,1H),4.85(d,J＝11.0Hz,1H),4.74(d,J＝12.1Hz,1H),4.66–4.57(m,3H),4.55(d,J＝12.1Hz,1H),4.46(dd,J＝12.2,2.4Hz,1H),4.35(dt,J＝10.0,3.0Hz,1H),4.23(dd,J＝12.2,3.6Hz,1H),4.13–4.06(m,1H),3.98–3.83(m,3H),3.77(d,J＝10.2Hz,1H),3.56(dd,J＝9.6,3.4Hz,1H),3.44(s,3H)；13C NMR(100MHz)δ166.02,165.50,165.28,164.82,138.17,137.87,137.78,133.37,133.23,133.08,132.94,129.88,129.79,129.70,129.32,129.04,128.96,128.46,128.39,128.37,128.33,128.21,128.15,128.05,127.96,127.60,127.53,127.49,127.17,98.89,97.87,81.34,80.14,76.14,75.35,73.48,73.29,70.38,69.84,69.54,69.48,69.11,66.62,62.61,55.33.
实施例3
1、糖基供体的合成
(1)将3.79g(5.40mmol)全苯甲酰化葡萄糖、1.52g(6.49mmol)邻碘苄醇以30mL二氯甲烷溶解，室温下，向该溶液中加入0.49mL(2.70mmol)三氟甲磺酸三甲基硅酯，室温反应6小时后，TLC表明反应已完全，柱色谱分离(V乙酸乙酯:V石油醚＝1/4洗脱液)纯化，得到3.80g化合物21，产率为86％。
Figure BDA0003717667460000141
(2)称取70mg(0.086mmol)化合物21于50mL圆底烧瓶中，分别加入8.13mg(0.031mmol)三苯基膦、11.3mg(0.016mmol)三苯基膦氯化钯、3.1mg(0.016mmol)CuI，然后加入0.72mL DMF和0.72mL二异丙胺溶解底物，接着将反应液冷冻排氧气三次后，置烧瓶于室温条件下滴加45.6mg(0.345mmol)4-乙炔基苯甲醚，搅拌反应4h后TLC监测反应结束，用饱和NH4Cl水溶液淬灭反应，反应放热并产生灰色沉淀，接着用去离子水洗涤三次除去Cu2+，乙酸乙酯萃取三次合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1/2.5洗脱液)，得到63.3mg黄色糖浆状化合物22，产率为90％。
Figure BDA0003717667460000151
化合物22的表征数据为：1H NMR(400MHz,CDCl3)δ8.00(dd,J＝8.3,1.4Hz,2H),7.87–7.81(m,6H),7.53–7.36(m,8H),7.36–7.23(m,8H),7.20(td,J＝7.6,1.4Hz,1H),7.04(td,J＝7.7,1.5Hz,1H),6.86–6.78(m,2H),5.85(t,J＝9.6Hz,1H),5.72(t,J＝9.7Hz,1H),5.63(dd,J＝9.7,7.9Hz,1H),5.07(s,2H),4.95(d,J＝7.9Hz,1H),4.60(dd,J＝12.1,3.3Hz,1H),4.43(dd,J＝12.1,4.7Hz,1H),4.11(ddd,J＝9.7,4.7,3.3Hz,1H),3.79(s,3H)；13C NMR(100MHz,CDCl3)δ166.10,165.78,165.12,165.07,159.73,138.00,133.36,133.19,133.08,133.04,132.94,131.74,129.81,129.77,129.74,129.69,129.50,129.18,128.76,128.35,128.31,128.25,128.17,128.08,127.66,122.51,114.93,114.02,99.70,94.17,85.40,72.91,72.22,71.74,69.67,68.99,63.02,55.26.
2、糖类受体的糖基化反应
向45.7mg(0.056mmol)化合物22及20mg(0.043mmol)化合物13的混合物中依次加入50mg
Figure BDA0003717667460000152
分子筛及1.4mL二氯甲烷，冰浴冷却10分钟后，向该溶液中依次加入14.5mg(0.0645mmol)N-碘代丁二酰亚胺和0.13mL0.1mol/L三氟甲磺酸三甲基硅酯的二氯甲烷溶液，室温反应半小时后，TLC表明反应已完全，硅胶柱色谱分离，得到44.2mg化合物23，产率为99％。
Figure BDA0003717667460000153
化合物23的表征数据为：1H NMR(400MHz,CDCl3)δ7.99(dd,J＝8.5,1.4Hz,2H),7.90–7.87(m,4H),7.82(dd,J＝8.5,1.4Hz,2H),7.54–7.47(m,2H),7.43–7.19(m,23H),7.04(dd,J＝7.1,2.4Hz,2H),5.88(t,J＝9.6Hz,1H),5.67(t,J＝9.7Hz,1H),5.59(dd,J＝9.7,7.8Hz,1H),4.89(d,J＝11.0Hz,1H),4.81(d,J＝7.8Hz,1H),4.73(d,J＝12.0Hz,1H),4.68(d,J＝10.9Hz,1H),4.63–4.57(m,2H),4.54–4.46(m,3H),4.27(d,J＝11.1Hz,1H),4.14(d,J＝8.8Hz,1H),4.10–4.06(m,1H),3.88(t,J＝9.3Hz,1H),3.77–3.69(m,2H),3.43(dd,J＝9.6,3.5Hz,1H),3.37(t,J＝9.3Hz,1H),3.20(s,3H)；13C NMR(100MHz,CDCl3)δ166.10,165.83,165.14,164.91,138.74,138.14,138.09,133.42,133.24,133.13,133.09,129.79,129.72,129.69,129.50,129.11,128.73,128.68,128.41,128.38,128.33,128.31,128.28,128.24,128.09,127.85,127.57,127.43,101.28,97.91,81.83,79.69,77.21,75.51,74.67,73.34,72.80,72.15,71.75,69.73,69.41,68.26,63.20,54.98,29.67。
实施例4
将52.8mg(0.0646mmol)化合物24(制备过程与化合物22相同)、20mg(0.043mmol)化合物13溶解于0.86mL二氯甲烷，室温下，向该溶液中依次加入0.7μL(0.0043mmol)三氟甲磺酸酐，室温反应2h，TLC表明反应已完全，柱色谱分离(V乙酸乙酯:V石油醚＝1:3洗脱液)，得40.56mg化合物25，产率为90％。
Figure BDA0003717667460000161
化合物25的表征数据为：1H NMR(400MHz,)δ8.11–8.05(m,2H),8.03–7.98(m,2H),7.91–7.85(m,2H),7.80–7.73(m,2H),7.64–7.57(m,1H),7.57–7.51(m,1H),7.50–7.44(m,2H),7.44–7.36(m,5H),7.16–7.08(m,2H),5.96(d,J＝3.4Hz,1H),5.84(dd,J＝10.4,8.0Hz,1H),5.59(dd,J＝10.4,3.5Hz,1H),4.89(d,J＝10.9Hz,1H),4.75(d,J＝8.0Hz,1H),4.74–4.63(m,3H),4.60–4.52(m,2H),4.49(d,J＝3.5Hz,1H),4.43–4.33(m,2H),4.27–4.17(m,2H),3.89(t,J＝9.2Hz,1H),3.78–3.71(m,2H),3.42–3.32(m,2H),3.20(s,3H)；13C NMR(100MHz,)δ165.98,165.58,165.55,165.53,165.09,138.72,138.15,138.09,133.56,133.27,133.11,130.03,130.01,129.74,129.72,129.65,129.35,129.34,129.21,129.19,128.95,128.94,128.64,128.63,128.58,128.56,128.45,128.44,128.41,128.40,128.37,128.36,128.32,128.26,128.24,128.06,128.05,128.00,127.87,127.86,127.84,127.83,127.66,127.52,127.52,127.51,127.46,125.80,125.41,101.96,97.85,97.83,81.86,79.76,77.39,77.20,75.50,74.67,73.32,71.56,71.28,69.65,69.52,68.62,68.01,61.81,54.96.
实施例5
1、糖基供体的合成
称取41.21mg(0.06mmol)化合物11与24.8mg(0.04mmol)化合物9于5mL圆底烧瓶中，与甲苯共沸除水三次，加入磁子，抽真空2h，加入1mg(0.002mmol)三氟甲磺酸汞，并加入无水二氯甲烷溶解底物，在室温下搅拌。经TLC薄层板监测反应完全后，加少量三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后柱色谱分离(V乙酸乙酯:V石油醚＝1/1.5洗脱液)，得到38.77mg白色泡沫状β构型化合物26，产率为90％。
Figure BDA0003717667460000171
化合物26的表征数据：
Figure BDA0003717667460000172
(c 1.00,CHCl3)；IR(KBr)ν(cm-1)3030,2949,2919,2867,1751,1454,1362,1121,1058,739,697；1H NMR(400MHz,CDCl3)δ7.83(dd,J＝7.6,0.8Hz,1H),7.48(d,J＝7.2Hz,1H),7.40(d,J＝7.2Hz,2H),7.35-7.20(m,21H),6.92(td,J＝7.6,1.2Hz,1H),5.50(t,J＝9.6Hz,1H),5.44(d,J＝7.2Hz,1H),4.84(d,J＝12.4Hz,1H),4.75(d,J＝12.4Hz,1H),4.62(d,J＝10.4Hz,2H),4.57(s,1H),4.54-4.40(m,6H),4.08(d,J＝13.6Hz,2H),3.97(d,J＝13.2Hz,1H),3.89(d,J＝2.4Hz,1H),3.82(d,J＝9.6Hz,1H),3.74(dd,J＝7.2,2.8Hz,1H),3.64(d,J＝8.0Hz,3H),3.54(s,3H),3.48(dd,J＝9.6,2.4Hz,1H),2.71(t,J＝6.8Hz,2H),2.62-2.49(m,2H),2.16(s,3H)；13C NMR(100MHz,CDCl3)δ206.08,171.47,169.43,167.56,140.57,139.58,138.16,138.04,137.69,137.60,130.37,128.65,128.31,128.26,128.20,128.15,128.10,128.08,128.04,127.78,127.70,127.65,127.50,127.42,127.39,100.93,100.57,80.07,77.97,77.20,76.57,75.10,74.05,73.76,73.34,72.82,72.62,72.14,71.58,68.91,52.44,52.08,39.73,37.67,29.76,27.77；13C-GATED(100MHz,CDCl3)100.93,(1JC1,H1＝158.9Hz,C-1),80.07,(1JC1’,H1’＝164.5Hz,C-1’)；HRMS(ESI)C54H57NaIO14S[M+Na]+:理论值1111.2406,实测值1111.2408。
称取171.3mg(0.16mmol)化合物26于10mL圆底烧瓶中，分别加入14.8mg(0.056mmol)三苯基膦、19.8mg(0.028mmol)三苯基膦氯化钯、5.4mg(0.028mmol)CuI，之后加入2.7mL DMF和2.7mL二异丙胺溶解底物，接着将反应液冷冻排氧三次，置反应瓶于室温条件下滴加61μL(0.47mmol)4-乙炔基苯甲醚，搅拌4h后待TLC监测反应结束，用饱和NH4Cl水溶液淬灭反应，反应放热并产生灰色沉淀，接着用去离子水洗涤三次除去Cu2+，乙酸乙酯萃取三次并合并有机相，有机相经盐洗、无水Na2SO4干燥、过滤、浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1/1.5洗脱液)，得到157.7mg白色泡沫状化合物27，产率为92％。
Figure BDA0003717667460000181
化合物27的表征数据：
Figure BDA0003717667460000182
(c 0.81,CHCl3)；IR(KBr)ν(cm-1)3025,2953,2918,2855,1746,1509,1455,1364,1248,1109,741,697；1H NMR(400MHz,CDCl3)δ7.54-7.42(m,4H),7.38(d,J＝7.2Hz,2H),7.35-7.26(m,5H),7.24(d,J＝2.8Hz,7H),7.22-7.16(m,8H),6.88-6.82(m,2H),5.53-5.44(m,2H),4.82(d,J＝12.4Hz,1H),4.72(d,J＝12.4Hz,1H),4.62(t,J＝5.8Hz,2H),4.54(d,J＝12.2Hz,2H),4.50(d,J＝4.2Hz,1H),4.46(d,J＝8.4Hz,2H),4.42(d,J＝1.4Hz,1H),4.39(d,J＝2.4Hz,1H),4.18(d,J＝12.8Hz,1H),4.12(d,J＝13.2Hz,1H),3.87(d,J＝2.6Hz,1H),3.83-3.77(m,4H),3.72(dd,J＝6.6,2.8Hz,1H),3.64(d,J＝5.8Hz,1H),3.60(d,J＝5.6Hz,3H),3.53(s,3H),3.46(dd,J＝9.6,2.8Hz,1H),2.73-2.67(m,2H),2.57-2.52(m,2H),2.17(s,3H)；13C NMR(100MHz,CDCl3)δ206.08,171.47,169.53,167.57,159.58,139.87,138.21,138.10,137.70,137.62,132.97,131.95,129.32,128.92,128.29,128.24,128.21,128.09,128.08,128.03,128.00,127.93,127.75,127.67,127.57,127.49,127.42,127.36,127.33,126.90,123.31,115.28,113.88,101.06,94.71,86.16,80.40,78.03,77.20,75.16,74.10,73.89,73.31,72.70,72.44,72.02,71.53,68.88,55.18,52.40,52.04,37.65,33.20,29.74,27.76；HRMS(ESI)C62H80NaO11[M+Na]+:理论值1115.3858,实测值1115.3843。
2、糖类受体的糖基化反应
称取90.7mg(0.083mmol)化合物26于10mL圆底烧瓶中，与甲苯共沸除水三次，抽真空换氩气三次后，加入2.7mL无水二氯甲烷、0.7mL无水吡啶溶解底物，再加入90.7mg(0.083mmol)醋酸肼，室温下搅拌2h，TLC监测反应结束，加少量丙酮溶液淬灭反应，二氯甲烷稀释反应液，1M HCl水溶液洗涤两次除去大量吡啶，二氯甲烷萃取水相三次合并有机相，最后有机相经盐洗、无水Na2SO4干燥、过滤，浓缩、柱色谱分离(V乙酸乙酯:V石油醚＝1.5/1洗脱液)，得到72.7mg黄色糖浆状化合物28，产率为91％。
Figure BDA0003717667460000191
化合物28的结构表征数据：
Figure BDA0003717667460000192
(c 0.74,CHCl3)；IR(KBr)ν(cm-1)3021,2944,2913,2855,1746,1450,1356,1116,1056,736,696；1H NMR(400MHz,CDCl3)δ7.84(dd,J＝8.0,0.8Hz,1H),7.49(d,J＝7.2Hz,1H),7.40(d,J＝7.0Hz,2H),7.36-7.27(m,8H),7.26-7.19(m,11H),6.93(td,J＝7.6,1.2Hz,1H),5.45(d,J＝7.2Hz,1H),4.85(d,J＝12.2Hz,1H),4.73(d,J＝12.2Hz,1H),4.63(d,J＝6.4Hz,1H),4.61(d,J＝3.4Hz,1H),4.59-4.53(m,3H),4.51(d,J＝4.0Hz,1H),4.49-4.41(m,3H),4.26(t,J＝9.6Hz,1H),4.09(d,J＝13.4Hz,2H),3.98(d,J＝13.6Hz,1H),3.89(d,J＝2.8Hz,1H),3.75-3.73(m,1H),3.72(d,J＝6.4Hz,1H),3.70(s,3H),3.56(s,3H),3.34(dd,J＝9.6,2.8Hz,1H),2.96(s,1H)；13C NMR(100MHz,CDCl3)δ206.08,171.46,169.41,167.55,140.56,139.57,138.15,138.02,137.67,137.59,130.36,128.64,128.30,128.19,128.14,128.09,128.07,128.03,127.77,127.69,127.64,127.49,127.42,127.38,100.56,77.95,75.07,74.04,73.73,73.33,72.80,72.12,71.57,68.89,52.44,52.07,39.72,37.66,29.76,27.76；HRMS(ESI)C49H51INaO12S[M+Na]+:理论值1013.2038,实测值1013.2035。
称取98.39mg(0.09mmol)化合物27与59.45mg(0.06mmol)化合物28于5mL圆底烧瓶中，加入1.2mL无水二氯甲烷溶解底物，然后加入54μL(0.006mmol)三氟甲磺酸。室温下搅拌2h后，加三乙胺淬灭反应，旋干溶剂，核磁粗谱判断选择性，之后柱色谱分离(V乙酸乙酯:V石油醚＝1.5:1洗脱液)，得到79.3mg呈白色泡沫状化合物29，产率为72％。
Figure BDA0003717667460000201
化合物29的表征数据：
Figure BDA0003717667460000202
(c 0.32,CHCl3)；IR(KBr)ν(cm-1)3060,3031,2956,2925,2856,1752,1495,1453,1364,1262,1059,801,739,699；1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.0Hz,1H),7.49(d,J＝7.2Hz,1H),7.42(t,J＝7.2Hz,2H),7.36(d,J＝7.2Hz,2H),7.32-7.27(m,13H),7.24-7.22(m,12H),7.21-7.17(m,12H),6.93(td,J＝7.6,1.2Hz,1H),5.51-5.49(m,1H),5.47-5.42(m,2H),4.88-4.85(m,1H),4.82(d,J＝12.8Hz,1H),4.75(d,J＝12.0Hz,2H),4.70(s,1H),4.66(d,J＝12.6Hz,1H),4.60(d,J＝6.4Hz,1H),4.56(d,J＝2.8Hz,2H),4.53(d,J＝5.2Hz,2H),4.50(s,1H),4.48-4.46(m,2H),4.44(d,J＝5.2Hz,1H),4.41(d,J＝4.6Hz,2H),4.38(d,J＝6.8Hz,3H),4.35-4.28(m,2H),4.20(d,J＝6.4Hz,1H),4.08(d,J＝12.8Hz,2H),3.98(d,J＝12.8Hz,2H),3.89(dd,J＝10.4,2.4Hz,1H),3.83-3.78(m,2H),3.75(d,J＝9.6Hz,3H),3.71(dd,J＝7.6,2.4Hz,1H),3.69-3.65(m,1H),3.65-3.52(m,13H),3.43(dd,J＝9.8,2.4Hz,2H),2.70(t,J＝6.4Hz,2H),2.58-2.50(m,2H),2.16(d,J＝3.6Hz,3H)；13C NMR(100MHz,CDCl3)δ206.25,171.56,169.81,169.53,168.20,167.69,139.63,138.75,138.50,138.34,138.26,138.05,137.80,137.72,137.66,130.47,128.70,128.36,128.29,128.21,128.13,128.08,127.99,127.83,127.73,127.59,127.54,127.42,127.36,127.27,127.24,100.65,78.10,77.98,77.21,75.70,75.48,75.40,75.19,75.06,74.47,74.39,74.23,74.15,74.00,73.72,73.43,73.35,72.87,72.78,72.51,72.36,72.29,72.22,71.57,71.47,71.33,68.91,52.44,52.35,52.26,52.16,39.79,37.76,29.67,27.83；HRMS(ESI)C96H101INaO26S[M+Na]+:理论值1851.5239,实测值1851.5237。

Claims (7)

1.一种基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：将式I所示邻炔基苄醚类糖基供体与亲核试剂R'-H溶解于非质子性有机溶剂中，并加入催化剂或促进剂室温反应，得到式II所示糖苷；
Figure FDA0003717667450000011
式中PG代表保护基，X为O或S原子，R为对甲氧基苯基或正丁基；X’为O、N或S原子；R’代表亲核试剂的亲电基团，H代表氢原子。
2.根据权利要求1所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：所述邻炔基苄醚类糖基供体与亲核试剂、催化剂或促进剂的摩尔比为1:1.2～2.0:0.05～2。
3.根据权利要求1或2所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：所述亲核试剂为糖类的伯醇或仲醇，或者非糖类的伯醇、仲醇或叔醇，或者含硫或含氮类亲核试剂。
4.根据权利要求1或2所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：所述催化剂是三氟甲磺酸、三氟甲磺酸酐、三氟甲磺酸铜、三氟甲磺酸汞中任意一种，促进剂为N-碘代丁二酰亚胺和三氟甲磺酸。
5.根据权利要求1所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：所述保护基为乙酰基、苯甲酰基、新戊酰基、苄基、硅基任意一种或多种糖类保护基团的组合。
6.根据权利要求1所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：所述非质子性有机溶剂为四氢呋喃、乙醚、甲苯、1,2-二氯乙烷、二氯甲烷、乙腈中任意一种。
7.根据权利要求1所述的基于邻炔基苄醚类糖基供体的高效糖基化方法，其特征在于：室温反应的时间为0.5～24小时。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070219161A1 (en) * 2004-03-26 2007-09-20 Junichi Tamura Preparation Process Of Oligoglycosaminoglycan, And Reducing End Glucuronic Acid Type Oligochondroitin Sulfate And Pharmaceutical Composition Comprising The Same
US20130158242A1 (en) * 2011-12-16 2013-06-20 National Chiao Tung University Alpha-selective glycosylation method
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
CN107056854A (zh) * 2017-06-12 2017-08-18 江西师范大学 一种邻炔基酚醚类糖苷化给体及其制备方法和应用
CN109912672A (zh) * 2019-04-02 2019-06-21 江西师范大学 一种以邻炔基苯酚醚作为离去基的碱基糖苷化的方法
CN110615818A (zh) * 2019-09-27 2019-12-27 江西科技师范大学 氟达拉滨和奈拉滨的合成方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070219161A1 (en) * 2004-03-26 2007-09-20 Junichi Tamura Preparation Process Of Oligoglycosaminoglycan, And Reducing End Glucuronic Acid Type Oligochondroitin Sulfate And Pharmaceutical Composition Comprising The Same
US20130158242A1 (en) * 2011-12-16 2013-06-20 National Chiao Tung University Alpha-selective glycosylation method
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
CN107056854A (zh) * 2017-06-12 2017-08-18 江西师范大学 一种邻炔基酚醚类糖苷化给体及其制备方法和应用
CN109912672A (zh) * 2019-04-02 2019-06-21 江西师范大学 一种以邻炔基苯酚醚作为离去基的碱基糖苷化的方法
CN110615818A (zh) * 2019-09-27 2019-12-27 江西科技师范大学 氟达拉滨和奈拉滨的合成方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JINCAI WANG ET AL.: ""S‑o‑(p‑Methoxyphenylethynyl)benzyl (SMPEB) Glycosides for Catalytic Glycosylation and Their Application in the Synthesis of Polyporus Umbellatus Polysaccharides"", 《ORGANIC LETTERS》, vol. 25, pages 6116 *
XIAOPING CHEN ET AL.: ""ortho-(Methyltosylaminoethynyl)benzyl glycosides as new glycosyl donors for latent-active glycosylation"", 《CHEM. COMMUN.》, vol. 51, pages 13957 - 13960 *
XINGUANG LAN ET AL.: ""Tf2O/TfOH catalytic glycosylation using o-(p-methoxyphenylethynyl) benzyl glycosides as donors and its application in synthesis of oligosaccharides"", 《TETRAHEDRON LETTERS》, vol. 116, pages 154342 - 154346 *
YUJIA ZU ET AL.: ""n‑Pentenyl-Type Glycosides for Catalytic Glycosylation and Their Application in Single-Catalyst One-Pot Oligosaccharide Assemblies"", 《ORGANIC LETTERS》, vol. 21, pages 8270 - 8274 *

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