CN109912642A - 一种β-2-脱氧糖苷键的立体选择性合成的方法 - Google Patents
一种β-2-脱氧糖苷键的立体选择性合成的方法 Download PDFInfo
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- 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
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- 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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Abstract
本发明公开了一种β‑2‑脱氧糖苷键的立体选择性合成的方法,以3,4‑O‑异亚丙基‑6‑O‑叔丁基二苯基甲硅烷基‑D‑半乳糖烯为供体,与糖基受体和分子筛在促进剂存在条件下,进行糖苷化反应。其中,3,4‑O‑异亚丙基‑6‑O‑叔丁基二苯基甲硅烷基‑D‑半乳糖烯在3‑位和4‑位羟基上安装异亚丙基缩醛基保护基和在6‑位羟基上安装叔丁基二苯基硅基(TBDPS)保护基,通过上述保护基的协同作用,控制供体的糖环构象,实现β‑构型高立体选择性的合成。该方法可以有效高选择性控制糖苷化反应的立体选择性,底物适用范围广,操作方便,原料易得,糖苷化反应的副反应少,目标产物产率高且光学纯度高,为糖苷化反应的研究提供了一种新的设计思路。
Description
技术领域
本发明属于天然寡糖链合成的技术领域,具体涉及一种β-2-脱氧糖苷键的立体选择性合成的方法。
背景技术
2-脱氧糖苷是指糖苷中糖基单元的2-位羟基被氢原子取代的糖苷,其广泛存在于自然界,是构成各种抗生素(大环内酯类、蒽环类、金霉酸类、红霉素和烯二炔类)以及强心苷、C21甾体皂苷等糖类化合物糖链的重要结构单元。2-脱氧糖苷是许多天然产物和抗肿瘤药物的有效成分,鉴于具有重要生物功能和药理生物活性,因此,合成天然的2-脱氧糖苷及其衍生物并探索其生物学意义对脱氧糖类新药开发具有重大的指导意义。
天然产物2-脱氧糖苷在自然界中提取所得到的量有限,远远不能满足研究的需求,因此通过化学方法大量制备成为了获得该类化合物的有效手段。越来越多的化学工作者、药物研发人员致力于通过化学合成方法来得到2-脱氧糖苷,其中,糖苷键的立体选择性合成则是2-脱氧糖苷合成的关键,但糖苷键的立体选择是最具有挑战性的。因为存在以下问题:(1)糖环上2位缺少邻基参与集团,糖苷键构型主要由异头碳效应控制,所以无法有效控制2-脱氧糖苷键的构型,经常得到两种混合构型的产物,分离纯化比较困难;(2)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。然而,现有的2-脱氧糖苷合成方法虽然在立体选择性等方面已取得不小进展,实现了一些复杂天然糖苷的合成,但仍然存在如下问题:现有方法在某一条件下只针对某一型的苷键,方法的普适性仍有不足,所以对新的、实用范围广的立体选择性糖苷化方法需求很迫切。目前α-2-脱氧糖糖苷键的构建方法现在已经比较成熟,但是相比之下β-2-脱氧糖糖苷键的立体选择性合成仍然具有很高的挑战性,而且关于β-2-脱氧糖糖苷键的立体选择性合成也鲜有报道。
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-脱氧糖苷键的立体选择性合成的方法,解决现有方法β-2-脱氧糖糖苷键的立体选择性差和底物适用性不佳的问题。
为实现上述目的,本发明采用如下技术方案:一种β-2-脱氧糖苷键的立体选择性合成的方法,将糖基供体、糖基受体及新鲜活化的分子筛加入有机溶剂中冷却至-50℃,得到悬浮液,再将所述悬浮液搅拌10~20min,然后加入促进剂继续搅拌1~2h,再将上述混合物逐渐温热至0℃并用三乙胺淬灭,经干燥、过滤和真空浓缩即得到β-2-脱氧糖苷类化合物,所述糖基供体为3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯,其化学结构式如下所示:
这样,3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯在促进剂存在条件下,3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯中3-位和4-位羟基上的异亚丙内酯缩醛和6-位羟基上的大位阻叔丁基二苯基硅基相互协同作用下,使得糖环的β-面位阻较大,碘离子主要从α-面进攻烯键,得到α-面的桥卤离子中间体,最后受体从桥卤离子的背面进攻,从而得到β-构型的产物。
进一步,所述糖基受体为吡喃型糖类或呋喃型糖类;所述分子筛为3A分子筛或4A分子筛。
进一步,所述有机溶剂为二氯甲烷、乙腈、甲醇、丙酮、吡啶或二甲基甲酰胺;所述促进剂为N-碘代丁二酰亚胺、三氟甲磺酸三甲基硅脂、溴化氢醋酸溶液、对甲苯磺酸吡啶盐或咪唑中的一种或多种。
进一步,所述糖基供体、糖基受体和分子筛的摩尔比为1~2:1~2:2~4,可以减少糖苷化反应的副反应,提高目标产物的产率至80%以上。
进一步,所述3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯的合成路线如下:
具体包括以下步骤:
1)将D-半乳糖加入无水乙酸钠中,并在乙酸酐条件下回流反应,反应完全后,待体系冷却后倒入冰水中搅拌,经水洗、减压抽滤和烘干得到化合物a;
2)在冰浴条件下,将化合物a加入二氯甲烷中,充分溶解后,滴加溴化氢醋酸溶液,反应完全后,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥和减压蒸馏得到化合物b;
3)冰盐浴条件下,将化合物b加入锌粉和50%醋酸溶液的体系中反应,反应完全后,调节pH至中性,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥和减压蒸馏得到化合物c;
4)将化合物c加入甲醇,搅拌使其溶解,随后加入甲醇钠常温反应,反应完全后,调节反应液的pH至中性或弱碱性,再经减压蒸馏和柱层析分离得到化合物d;
5)冰浴条件下,以N,N-二甲基甲酰胺为溶剂,咪唑为催化剂,使化合物d与和叔丁基二苯基氯硅烷反应一段时间后逐渐升至室温反应,反应完全后,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥、减压蒸馏和柱层析分离得到化合物e;
6)冰浴条件下,将化合物e溶解于丙酮中,然后加入2.2-二甲氧基丙烷和对甲苯磺酸吡啶鎓,于20℃条件下反应,再经水洗、无水硫酸钠干燥、减压蒸馏和柱层析分离即得到所述的3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯。
通过化学反应在D-吡喃半乳糖烯的3-位和4-位羟基上安装异亚丙基缩醛基的同时在6-位羟基上安装叔丁基二苯基硅基(TBDPS),利用上述环状保护基和大位阻保护基效应,控制供体的糖环构象,可以高选择性控制糖苷化反应的立体选择性,从而实现了β-构型的合成。
进一步,步骤1)中所述D-半乳糖与无水乙酸钠的摩尔比为1~2:0.9~1.8。
进一步,步骤2)中所述化合物a与溴化氢醋酸溶液中溴化氢的摩尔比为1~2:13~26;所述溴化氢醋酸溶液的质量浓度为30~35%。
进一步,步骤3)中所述化合物b、锌粉和醋酸溶液的质量体积比为1~2g:1~2g:6~12ml;步骤4)中所述化合物c与甲醇钠的摩尔比为1~2:0.5~1。
进一步,步骤5)中所述化合物d与和叔丁基二苯基氯硅烷的摩尔比为1~2:1.1~2.2。
进一步,步骤6)中所述化合物e、2.2-二甲氧基丙烷和对甲苯磺酸吡啶鎓的摩尔比为1~2:9~18:0.05~0.1。
相比现有技术,本发明具有如下有益效果:
1、本发明以化合物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯为供体,与其它不同糖基受体进行糖苷化反应,通过TLC和NMR光谱检测产物中均未检测到异构的α-构型,β-构型的异构体为唯一产物,而且该方法适用于含有2-脱氧-β-吡喃半乳糖苷键的寡糖、二糖和多糖的制备。该方法可以有效高选择性控制糖苷化反应的立体选择性,具有底物适用范围广,操作方便、原料易得,糖苷化反应的副反应少,目标产物产率高且光学纯度高,得到了比较理想的实验结果,为糖苷化反应的研究提供了一种新的设计思路。
2、本发明制备的化合物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯,在3-位和4-位羟基上安装异亚丙基缩醛基且在6-位羟基上安装叔丁基二苯基硅基(TBDPS)的保护基组合,通过上述保护基的协同作用,控制供体的糖环构象,使得糖环的β-面位阻较大,碘离子主要从α-面进攻烯键,得到α-面的桥卤离子中间体,最后受体从桥卤离子的背面进攻,实现β-构型高立体选择性的合成,另外同时6-位羟基上安装叔丁基二苯基硅基,大大的扩展了反应底物。成功的找到了一组保护基能通过构象受限实现β-构型的合成。供体制备过程反应条件简单易控、操作方便、反应原料廉价易得,各阶段产物产率高,有利于工业化生产,在医药、材料和有机化工中具有潜在的应用价值。也为后续高选择性立体合成糖苷键的研究奠定了基础。
3、本发明制备的化合物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯的各个保护基之间可以在酸性或碱性条件下实现选择性脱除,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。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明。以下实施例中未对实验方法进行特别说明的,均为常规操作,所用试剂为普通市售。
3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯的合成路线如下:
具体包括以下步骤:
(1)按化学计量比称量D-半乳糖(20.0g,55.5mmol)加入圆底烧瓶(500ml)中,随后向其中加入无水乙酸钠(4.0g 48.8mmol),乙酸酐(40.0ml)条件下回流反应2h,通过薄层层析法判断反应完全(石油醚:乙酸乙酯=3:1),待体系冷却后倒入冰水中搅拌(300r/min,下同)除去乙酸酐然后再减压抽滤得到固体产物,水洗三次后再用无水乙醇洗一次,最后将减压抽滤得到的固体产物置于50℃的条件下烘干12h制备得到产物化合物a(全乙酰半乳糖)(36.1g,79.7mmol),产率为83.2%。
(2)化合物a(10.0g,25.6mmol)加入250ml圆底烧瓶中,加入干燥的二氯甲烷(50.0ml)在冰浴条件下搅拌使其溶解然后在遮光条件下滴加33%溴化氢醋酸溶液(HBr-CH3COOH)滴加完后反应2h通过薄层层析法判断反应完全(石油醚:乙酸乙酯=3:1),用二氯甲烷将体系稀释,再逐量加入饱和的NaHCO3溶液中和体系至中性,待分层后保留有机层,水层再用二氯甲烷萃取两次,合并有机层,有机层再用饱和食盐水洗一次,无水硫酸钠干燥有机层,减压蒸馏(-0.09MPa,45℃)除去多余溶剂旋干得淡黄色浆状产物化合物b(全乙酰半乳溴代糖)(9.2g,22.3mmol),产率为87.1%。
(3)冰盐浴条件下,将化合物b(9.2g,22.3mmol)加入锌粉(10.4g,160.6mmol)和50%醋酸溶液(56.5ml)的体系中反应4h,通过薄层层析法判断反应完全(石油醚:乙酸乙酯=3:1),反应完后,向体系中加入二氯甲烷稀释,然后减压抽滤除去锌粉,向滤液中逐量加入饱和碳酸氢钠溶液,调节pH至中性,分液保留有机层,水层再用二氯甲烷萃取两次,合并有机层,有机层用饱和食盐水溶液洗一次,无水硫酸钠干燥,减压蒸馏(-0.09MPa,45℃)除去多余溶剂旋干得淡黄色浆状产物化合物c(全乙酰半乳烯糖)(5.5g,20.2mmol),产率为91.6%。
(4)将上一步所得的粗产品化合物c(5.5g,20.2mmol)加入圆底烧瓶(250ml)中,随后向其中加入甲醇(84.0ml),搅拌使其溶解,随后加入甲醇钠(0.55g,10.2mmol),常温反应1-2h,常温条件下反应脱除乙酸基(Ac)通过薄层层析法判断反应完全(二氯甲烷:甲醇=10:1),反应完全后,加入醋酸调节pH至中性或弱碱性,减压蒸馏(-0.09MPa,45℃)除去多余溶剂旋干得淡黄色浆状产物粗品,硅胶柱层析法分离(二氯甲烷:甲醇=5:1)得到重要的中间体化合物d(全羟基半乳烯糖)(2.7g,18.5mmol),产率为77.1%。
(5)用干燥的N,N-二甲基甲酰胺(18ml)作为溶剂将上一步所得粗产品化合物d(2.7g,18.5mmol)溶解于圆底烧瓶(100ml)中,冰浴条件下向其中加入50℃减压抽滤0.5h后活化处理的咪唑(1.8g,27.0mmol)为催化剂和叔丁基二苯基氯硅烷(4.3ml,16.5mmol)反应一段时间后逐渐升至室温反应1h,通过薄层层析法判断反应完全(石油醚:乙酸乙酯=6:1),反应完后向体系加入甲醇(1.5ml)终止反应,减压蒸馏(-0.09MPa,45℃)除去多余溶剂,加入二氯甲烷稀释体系,水洗三次合并有机层,再用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏(-0.09MPa,45℃)除去多余溶剂旋干得淡黄色浆状产物粗品,硅胶柱层析法分离(石油醚:乙酸乙酯=8:1)以此得到化合物e(5.2g,13mmol),产率为91.2%。
(6)用丙酮(92.5ml)将中间体化合物e(5.2g,13mmol)溶解于圆底烧瓶(250ml),冰浴条件下搅拌一段时间后加入2.2-二甲氧基丙烷和对甲苯磺酸吡啶鎓,20℃条件下反应2h,通过薄层层析法判断反应完全(二氯甲烷:甲醇=10:1),反应完后减压蒸馏(-0.09MPa,45℃)除去多余丙酮,然后用二氯甲烷溶解产物粗品,用饱和碳酸氢钠溶液和水各洗一次,最后用饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏(-0.09MPa,45℃)除去多余溶剂旋干得淡黄色浆状产物粗品,硅胶柱层析法分离(石油醚:乙酸乙酯=1:1)以此得到糖基供体3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(4.8g,11.7mmol),产率为86.8%。 1H NMR(600MHz,CDCl3):δ7.71-7.67(m,4H),7.44-7.36(m,4H),6.35(d,J=6.6Hz,1H),4.78-7.76(m,1H),4.67(dd,J=6.0,3.0Hz,1H),4.47(d,J=6.0Hz,1H),4.04(t,J=7.2Hz,1H),3.98-3.92(m,2H),1.45(s,3H),1.37(s,3H),1.07(s,9H);13CNMR(150MHz,CDCl3):δ144.6,135.62,135.57,133.4,133.3,129.74,129.72,127.72,127.68,110.2,102.6,74.9,71.9,68.6,62.9,28.2,26.9,26.8,26.8,19.3;HRMS(ESI)calcd for C25H32O4Si[M+Na]+ 447.1968,found 447.1979。
实施例1
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(81mg,0.19mmol)、糖基受体2,3,4-三-O-苄基-α-D-吡喃葡萄糖苷(134mg,0.29mmol)和新鲜活化的4A分子筛(220mg)在干燥CH3CN:CH2Cl2(v:v=2:1,将2.9mL)冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(86mg,0.38mmol)和TMSOTf(52μL,0.29mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(10:1,石油醚-EtOAc)快速纯化粗物质,得到化合物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖基-(1→6)-2,3,4-三-O-苄基-α-D-吡喃葡萄糖苷,为浅糖浆(159mg,82.3%)。Rf 0.45(4:1,petroleumether–EtOAc). 1H NMR(600MHz,CDCl3):δ7.70(td,J=7.8,1.2Hz,4H),7.43-7.27(m,21H),4.98(d,J=10.8Hz,1H),4.96(d,J=11.4Hz,1H),4.87(d,J=10.8Hz,1H),4.82(d,J=10.8Hz,1H),4.80(d,J=12.0Hz,1H),4.65(d,J=11.4Hz,1H),4.63(d,J=3.6Hz,1H),4.50(q,J=4.8Hz,1H),4.35(d,J=3.6Hz,1H),4.07(d,J=6.0Hz,1H),4.06(d,J=10.8Hz,1H),4.00-3.87(m,4H),3.86(t,J=9.0Hz,1H),3.72(d,J=5.4Hz,1H),3.72-3.68(m,2H),3.57(dd,J=9.6,3.6Hz,1H),3.33(s,3H),1.47(s,3H),1.34(s,3H),1.04(s,9H);13C NMR(150MHz,CDCl3):δ138.74,138.66,135.60,135.56,133.3,133.2,129.8,129.7,128.5,128.4,128.1,128.0,127.9,127.7,127.66,127.61,127.59,110.1102.0,98.2,82.3,82.1,79.8,75.8,75.1,74.0,73.52,73.45,69.5,67.7,62.5,55.3,33.2,29.7,28.2,26.7,26.0,19.2;HRMS(ESI)calcd for C53H63IO10Si[M+Na]+ 1037.3132,found 1037.3121。可见,通过TLC和NMR光谱未检测到2-脱氧-2-碘-α-D-吡喃葡萄糖苷衍生物。
实施例2
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(52mg,0.12mmol)、糖基受体2,3,4-三-O-苯甲酰基-α-D-吡喃甘露糖苷(90mg,0.18mmol)和新鲜活化的4A分子筛(140mg)在干燥的试剂(VCH3CN:VCH2Cl2=2:1,1.8mL)中冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(55mg,0.24mmol)和TMSOTf(33μL,0.18mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(3:1,石油醚-EtOAc)快速纯化粗物质,得到产物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖-(1→6)-2,3,4-三-O-苯甲酰基-α-D-甘露糖苷(110mg,85.1%)。Rf 0.4(石油醚:乙酸乙酯=3:1)。 1H NMR(500MHz,CDCl3):δ8.14(dd,J=8.0,1.5Hz,2H),7.93(dd,J=8.0,1.5Hz,2H),7.83(dd,J=8.0,1.5Hz,2H),7.67-7.57(m,5H),7.49-7.32(m,12H),7.27(t,J=8.0Hz,2H),5.91(q,J=5.0Hz,1H),5.86(dd,J=10.0,3.0Hz,1H),5.00(d,J=1.5Hz,1H),4.53(dd,J=9.0,5.0Hz,1H),4.51(d,J=9.0Hz,1H),4.29-4.25(m,1H),4.08(s,1H),4.07(dd,J=7.5,2.0Hz,1H),3.93-3.83(m,3H),3.80(t,J=9.0Hz,1H),3.72(dd,J=11.5,6.0Hz,1H),3.55(s,3H),1.47(s,3H),1.34(s,3H),1.02(s,9H);13C NMR(125MHz,CDCl3):δ165.6,165.45,165.43,135.6,135.5,133.4,133.32,133.29,133.2,133.1,130.1,129.8,129.7,129.4,129.2,129.1,128.6,128.4,128.3,127.7,127.6,110.0,102.3,98.4,81.9,77.2,73.8,73.4,70.6,70.3,69.8,68.2,67.2,62.4,55.9,32.5,28.3,26.7,26.1,19.2;HRMS(ESI)calcd for C53H57IO13Si[M+Na]+ 1079.2510,found1079.2514.
实施例3
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(49mg,0.12mmol)、糖基受体2,3,4-三-O-苄基-α-D-吡喃半乳糖苷(80mg,0.17mmol)和新鲜活化的4A分子筛(130mg)在干燥的试剂(VCH3CN:VCH2Cl2=2:1,1.7mL)中冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(52mg,0.23mmol)和TMSOTf(31μL,0.17mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(3:1,石油醚-EtOAc)快速纯化粗物质,得到产物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖-(1→6)-2,3,4-三-O-苄基-α-D-半乳糖苷(102mg,87.4%)。Rf 0.4(石油醚:乙酸乙酯=3:1)。 1H NMR(500MHz,CDCl3):δ7.71-7.66(m,4H),7.47-7.26(m,16H),7.25(d,J=8.0Hz,2H),7.18-7.11(m,3H),4.92(d,J=11.0Hz,1H),4.82(dd,J=12.0,5.0Hz,2H),4.72(d,J=12.0Hz,1H),4.70(d,J=11.5Hz,1H),4.67(d,J=3.5Hz,1H),4.57(d,J=11.0Hz,1H),4.51(dd,J=9.0,5.0Hz,1H),4.43(d,J=9.5Hz,1H),4.15(dd,J=5.0,2.0Hz,1H),4.03(dd,J=9.0,3.5Hz,1H),3.97-3.83(m,6H),3.75-3.69(m,2H),3.61(dd,J=10.5,7.0Hz,1H),3.41(s,3H),1.52(s,3H),1.38(s,3H),1.04(s,9H);13C NMR(125MHz,CDCl3):δ138.8,138.6,138.5,135.6,135.5,133.3,133.1,129.83,129.78,128.4,128.3,128.2,128.14,128.1,127.8,127.68,127.66,127.6,127.53,127.51,110.0,102.0,98.8,82.0,78.9,77.2,76.3,75.4,74.6,73.5,73.4,73.3,69.1,68.5,62.2,55.8,33.3,28.4,26.7,26.1,19.2;HRMS(ESI)calcd for C53H63IO10Si[M+Na]+ 1037.3132,found1037.3115.
实施例4
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(44mg,0.10mmol)、糖基受体2,5-二-O-苯甲酰基-α-L-阿拉伯呋喃糖苷(58mg,0.16mmol)和新鲜活化的3A分子筛(110mg)在干燥的试剂(VCH3CN:VCH2Cl2=2:1,1.6mL)中冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(47mg,0.21mmol)和TMSOTf(29μL,0.16mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(4:1,石油醚-EtOAc)快速纯化粗物质,得到产物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖-(1→3)-2,5-二-O-苯甲酰基-α-L-阿糖胞苷(82mg,85.8%)。Rf 0.45(石油醚:乙酸乙酯=4:1)。 1H NMR(600MHz,CDCl3):δ7.98(dd,J=7.8,1.2Hz,2H),7.94(dd,J=7.8,1.2Hz,2H),7.65(dd,J=7.8,1.2Hz,2H),7.60-7.58(m,3H),7.44-7.26(m,9H),7.21(t,J=7.8Hz,2H),5.40(s,1H),5.15(s,1H),4.98(d,J=9.6Hz,1H),4.61(dd,J=9.6,5.4Hz,1H),4.55(d,J=1.8Hz,1H),4.54(s,1H),4.44(dd,J=9.6,3.6Hz,1H),4.35(d,J=5.4Hz,1H),4.14(dd,J=5.4,1.8Hz,1H),4.06-4.04(m,1H),3.91(dd,J=10.2,7.8Hz,1H),3.85(dd,J=10.2,6.0Hz,1H),3.80(t,J=9.6,Hz,1H),3.46(s,3H),1.52(s,3H),1.37(s,3H),0.95(s,9H);13C NMR(150MHz,CDCl3):δ166.1,165.6,135.7,135.6,135.5,133.5,133.2,133.1,132.9,129.8,129.7,129.2,128.5,128.2,127.7,127.6,110.1,106.9,101.2,82.8,82.1,82.0,80.8,73.7,73.4,63.3,62.3,54.9,32.5,32.0,29.7,29.4,28.4,26.8,26.7,26.0,22.7,19.1;HRMS(ESI)calcd for C45H51IO11Si[M+Na]+ 945.2143,found945.2142.
实施例5
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(51mg,0.12mmol)、糖基受体2,3,6-三-O-苄基-α-D-吡喃葡萄糖苷(84mg,0.18mmol)和新鲜活化的3A分子筛(140mg)在干燥的试剂(VCH3CN:VCH2Cl2=2:1,1.8mL)中冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(54mg,0.24mmol)和TMSOTf(34μL,0.18mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(4:1,石油醚-EtOAc)快速纯化粗物质,得到产物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖-(1→4)-2,3,6-三-O-苄基α-D-吡喃葡萄糖苷(101mg,82.8%)。Rf 0.3(石油醚:乙酸乙酯=4:1)。 1H NMR(500MHz,CDCl3):δ7.70(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),7.47-7.24(m,18H),7.06-7.02(m,3H),4.79(d,J=10.0Hz,1H),4.78(d,J=12.0Hz,1H),4.77(d,J=12.0Hz,1H),4.69(d,J=10.5Hz,1H),4.58(d,J=12.5Hz,1H),4.56(s,1H),4.44(d,J=12.0Hz,1H),4.34(d,J=9.5Hz,1H),4.30(dd,J=9.0,5.0Hz,1H),4.19(dd,J=11.0,3.0Hz,1H),4.08(dd,J=5.0,1.5Hz,1H),3.99(t,J=9.5Hz,1H),3.86(t,J=9.5Hz,1H),3.81(q,J=9.5Hz,2H),3.76-3.71(m,2H),3.69(t,J=9.0Hz,1H),3.59(t,J=7.5Hz,1H),3.45(dd,J=9.5,3.5Hz,1H),3.37(s,3H),1.50(s,3H),1.39(s,3H),1.04(s,9H);13C NMR(125MHz,CDCl3):δ138.9,138.5,137.9,135.7,135.5,133.3,133.2,129.72,129.69,128.6,128.5,128.3,128.2,128.03,127.96,127.73,127.7,127.2,109.9,100.0,98.5,82.0,80.1,77.2,75.7,74.9,73.6,73.5,73.3,73.0,69.6,68.7,61.8,55.3,34.6,28.5,26.8,26.1,19.2;HRMS(ESI)calcd for C53H 63IO10Si[M+Na]+ 1037.3132,found 1037.3127.
实施例6
将3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯(38mg,0.09mmol)、糖基受体2,3,6-三-O-苯甲酰基-α-D-呋喃半乳糖苷(81mg,0.13mmol)和新鲜活化的3A分子筛(140mg)在干燥的试剂(VCH3CN:VCH2Cl2=2:1,1.3mL)中冷却至-50℃。将悬浮液搅拌15分钟,然后加入NIS(40mg,018mmol)和TMSOTf(24μL,0.13mmol)。将反应混合物在相同温度下搅拌2小时。将反应混合物逐渐温热至0℃并用Et3N淬灭。将混合物用CH2Cl2稀释并加入Na2S2O3,通过硅藻土过滤并真空浓缩。通过柱色谱(4:1,石油醚-EtOAc)快速纯化粗物质,得到产物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-2-脱氧-2-碘-β-D-吡喃半乳糖-(1→5)-2,3,6-三-O-苯甲酰基-α-D-呋喃半乳糖苷(87mg,84.5%)。Rf 0.40(石油醚:乙酸乙酯=4:1)。 1H NMR(500MHz,CDCl3):δ8.09(d,J=8.0,2H),8.04(d,J=7.5Hz,2H),7.91(d,J=7.5Hz,2H),7.64-7.50(m,7H),7.47-7.26(m,12H),5.79(d,J=4.0Hz,1H),5.44(s,1H),5.21(s,1H),4.79(dd,J=11.5,7.5Hz,1H),4.75(d,J=9.5Hz,1H),4.69(dd,J=11.5,5.0Hz,1H),4.61-4.58(m,1H),4.52(dd,J=9.0,5.0Hz,1H),4.42(dd,J=4.0,2.5Hz,1H),4.16(dd,J=5.0,1.5Hz,1H),4.00-3.89(m,3H),3.70-3.64(ABq,J=13.5,7.0,3.0Hz,1H),3.49(ABq,J=13.0,6.5,3.0Hz,1H),1.60-1.51(m,2H),1.36-1.18(m,10H),1.32(s,3H),1.12(s,3H),0.99(s,9H),0.86(t,J=7.0Hz,3H);13C NMR(125MHz,CDCl3):δ166.2,165.5,165.4,135.6,135.4,133.4,133.32,133.1,133.0,130.0,129.83,129.81,129.6,129.5,128.5,128.4,128.3,127.6,127.5,109.8,105.6,102.3,82.7,82.2,81.2,77.9,77.2,75.9,73.8,73.2,67.4,64.4,61.8,33.4,31.8,29.5,29.4,29.3,28.0,26.7,26.2,25.9,22.7,19.2,14.1;HRMS(ESI)calcd for C60H71IO13Si[M+Na]+1177.3606,found 1177.3606.
综上,不同糖基受体与3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯进行糖苷化反应,得到相应的糖苷产物,通过TLC和NMR光谱检测产物中均未检测到异构的α-构型,β-构型的异构体为唯一产物,说明化合物3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯在反应中显示出有效控制糖苷键立体选择性的能力。而且该方法适用于含有2-脱氧-β-吡喃半乳糖苷键的寡糖、二糖和多糖的制备,具有普适性,应用范围广。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,将糖基供体、糖基受体及新鲜活化的分子筛加入有机溶剂中冷却至-50℃,得到悬浮液,再将所述悬浮液搅拌10~20min,然后加入促进剂继续搅拌1~2h,然后将上述混合物逐渐温热至0℃并用三乙胺淬灭,经干燥、过滤和真空浓缩即得到β-2-脱氧糖苷类化合物,所述糖基供体为3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯,其化学结构式如下所示:
2.根据权利要求1所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,所述糖基受体为吡喃型糖类或呋喃型糖类;所述分子筛为3A分子筛或4A分子筛。
3.根据权利要求1所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,所述有机溶剂为二氯甲烷、乙腈、甲醇、丙酮、吡啶或二甲基甲酰胺;所述促进剂为N-碘代丁二酰亚胺、三氟甲磺酸三甲基硅脂、溴化氢醋酸溶液、对甲苯磺酸吡啶盐和咪唑中的一种或多种。
4.根据权利要求1所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,所述糖基供体、糖基受体和分子筛的摩尔比为1~2:1~2:2~4。
5.根据权利要求1所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,所述3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯的合成路线如下:
具体包括以下步骤:
1)将D-半乳糖加入无水乙酸钠中,并在乙酸酐条件下回流反应,反应完全后,待体系冷却后倒入冰水中搅拌,经水洗、减压抽滤和烘干得到化合物a;
2)在冰浴条件下,将化合物a加入二氯甲烷中,充分溶解后,滴加溴化氢醋酸溶液,反应完全后,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥和减压蒸馏得到化合物b;
3)冰盐浴条件下,将化合物b加入锌粉和50%醋酸溶液的体系中反应,反应完全后,调节pH至中性,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥和减压蒸馏得到化合物c;
4)将化合物c加入甲醇,搅拌使其溶解,随后加入甲醇钠常温反应,反应完全后,调节反应液的pH至中性或弱碱性,再经减压蒸馏和柱层析分离得到化合物d;
5)冰浴条件下,以N,N-二甲基甲酰胺为溶剂,咪唑为催化剂,使化合物d与和叔丁基二苯基氯硅烷反应一段时间后逐渐升至室温反应,反应完全后,分离有机层,然后将所述有机层经水洗、无水硫酸钠干燥、减压蒸馏和柱层析分离得到化合物e;
6)冰浴条件下,将化合物e溶解于丙酮中,然后加入2.2-二甲氧基丙烷和对甲苯磺酸吡啶鎓,于20℃条件下反应,再经水洗、无水硫酸钠干燥、减压蒸馏和柱层析分离即得到所述的3,4-O-异亚丙基-6-O-叔丁基二苯基甲硅烷基-D-半乳糖烯。
6.根据权利要求2所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,步骤1)中所述D-半乳糖与无水乙酸钠的摩尔比为1~2:0.9~1.8。
7.根据权利要求2所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,步骤2)中所述化合物a与溴化氢醋酸溶液中溴化氢的摩尔比为1~2:13~26;所述溴化氢醋酸溶液的质量浓度为30~35%。
8.根据权利要求2所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,步骤3)中所述化合物b、锌粉和醋酸溶液的质量体积比为1~2g:1~2g:6~12ml;步骤4)中所述化合物c与甲醇钠的摩尔比为1~2:0.5~1。
9.根据权利要求2所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,步骤5)中所述化合物d与和叔丁基二苯基氯硅烷的摩尔比为1~2:1.1~2.2。
10.根据权利要求2所述β-2-脱氧糖苷键的立体选择性合成的方法,其特征在于,步骤6)中所述化合物e、2.2-二甲氧基丙烷和对甲苯磺酸吡啶鎓的摩尔比为1~2:9~18:0.05~0.1。
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