CN111995638B - 一类3-硫-1-烯糖类化合物的合成方法 - Google Patents
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- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明提供一种3‑硫‑1‑烯糖类化合物的合成方法，将催化剂、配体和半乳烯糖加入到有机溶剂及硫醇/酚中，加入锌粉，100‑120摄氏度下搅拌反应，TLC检测反应进程，当半乳烯糖原料完全消失后，终止反应，即可得到3‑硫‑1‑烯糖，所述的硫醇/酚的结构式为R2‑SH，其中R2的结构式包括亚甲基羧酸酯、苄基、烷基、苯基、取代苯基、五元或六元杂环基中的任意一种；R1包括硅基、烷基、C1‑C18烷基、苄基、苯基、三苯基甲基，吡啶基、苯甲酸酯，吡啶酸酯，喹啉甲酸酯中的任意一种。本发明采用了廉价的钴催化剂，添加合适的配体和溶剂有助于形成高活性的催化中间体，锌粉的加入促进钴催化剂的催化循环的顺利进行。
Description
技术领域
本发明主要关于一种3-硫-1-烯糖类化合物的合成方法。
背景技术
硫代糖在糖化学与药物化学研究领域占有重要地位。1-硫代糖是最常用的糖基供体之一，在各种糖基化反应均起到至关重要的作用，例如脂肪巯基(-SH)和芳硫基(-SAr)基团的单糖硫苷已被广泛用于单糖、寡糖和多糖以及糖肽、糖蛋白等糖缀合物的合成中。另外，据报道多种硫代糖被发现具有良好的药理活性，甚至已经被用作临床药物多年，例如口服抗风湿药物金诺芬，就是一类含有金元素的硫苷；萝卜硫素是当前抗肿瘤研究的明星分子之一。不仅1-硫代糖作为“合成砌块”应用广泛，而且3-硫代糖也在天然产物与药物合成中具有重要作用，例如张培成教授课题组在2018年首次采用含3-硫代糖类似物结构为中间体完成了具有良好药理活性的天然氧糖苷产物polyflavanostilbene B。但是目前研究1-硫代糖的研究比较多，而研究3-硫代糖寥寥无几，因此开发合成的高效3-硫代烯糖化合物方法意义重大。
已报道的为数不多的3-硫代烯糖的合成通常是1-硫糖的合成反应的副产物或者意外产物。1991年Waldemar Priebe教授报道了采用类似Macheal加成的方法将硫醇与烯糖反应生成了3-硫-1-烯鼠李糖，但是产物的立体选择性有待提高。2014年陈沛然教授采用Sm(OTf)3合成了一系列1-硫-2-烯糖与3-硫-1-烯糖，产率良好，不过区域选择性有待提高。
发明内容
针对上述技术问题，本发明采用廉价的钴催化剂与高活性的半乳烯糖供体开发出了一种高区域选择性与立体选择性的硫糖基化方法。
一种3-硫-1-烯糖类化合物的合成方法，包括如下步骤：将催化剂、配体和半乳烯糖加入到有机溶剂及硫醇/酚中，加入锌粉，100-120摄氏度下搅拌反应，TLC检测反应进程，当半乳烯糖原料完全消失后，终止反应，即可得到3-硫-1-烯糖，所述的反应式如下：
所述的硫醇/酚的结构式为R2-SH，其中R2的结构式包括亚甲基羧酸酯、苄基、烷基、苯基、取代苯基、五元或六元杂环基中的任意一种；R1包括硅基、烷基、C1-C18烷基、苄基、苯基、三苯基甲基，吡啶基、苯甲酸酯，吡啶酸酯，喹啉甲酸酯中的任意一种。
通常烯丙基化反应需要采用稀有的贵金属催化反应，本发明采用了廉价的钴催化剂，添加合适的配体和溶剂有助于形成高活性的催化中间体，锌粉的加入促进钴催化剂的催化循环的顺利进行。
所述的五元或六元杂环基包括2-嘧啶基、2-苯并噁唑、咪唑基中的任意一种。
所述的配体包括硅基、烷基C1-C4烷基、苄基、苯基，三苯基甲基，吡啶基、苯甲酸酯，吡啶酸酯，喹啉甲酸酯中的任意一种。
所述的催化剂包括CoCl2、CoBr2、Co(acac)2、Co(PPh3)2Cl2、Co(BF4)2·6H2O中的任意一种。
所述的溶剂包括四氢呋喃、乙醚、1,4-二氧六环、二氯甲烷、乙腈、N,N-二甲基甲酰胺、二甲基亚砜中的任意一种。
催化剂、配体、半乳烯糖、硫醇/酚的摩尔比为0.01-0.05：0.005-0.03：0.5-1：1-4。
采用本发明的方法制备得到的3-硫-1-烯糖类化合物，该类化合物的结构式为：
其中优选的结构式包括如下：
中的任意一种。
作为另一优选方案，本发明的化合物包括芳杂环类3-硫糖类化合物，其结构式包括如下：
附图说明
图1为实施例1所述化合物的氢谱。
图2为实施例1所述化合物的碳谱。
具体实施方式
实验试剂
四氟化硼钴(北京百灵威科技有限公司)、氯化钴与溴化钴(上海麦克林生化科技有限公司)、石油醚(沸程60-90℃，天津市恒兴化学试剂制造有限公司)、乙酸乙酯(分析纯，天津市科密欧化学试剂有限司)、无水硫酸钠(分析纯，国药集团化学试剂有限公司)、氘代氯仿-d(氘原子含量99.8％，TMS含量0.03％V/V，10*0.5mL/盒，瑞士ARMAR公司)；核磁管(5mm 100/pk 2ST500-8，美国Norell公司)。
实验仪器
ZXZ-4型旋片式真空泵(临海市谭氏真空设备有限公司)、DZF-6020型真空干燥箱(上海新苗医疗器械制造有限公司)、SHB-IIIA循环水式多用途真空泵(上海豫康科教仪器设备有限公司)、CL-4型平板磁力搅拌器(郑州长城科工贸有限公司)、EYELA SB-1100旋转蒸发仪 (上海爱朗仪器有限公司)、FA2104B分析天平(上海越平科技仪器有限公司)、XRC-1型微熔点测定仪(四川大学科仪厂)、DF-101S集热式恒温加热磁力搅拌器(巩义市英峪予华仪器厂)、GZX-9240MBE数显鼓风干燥箱(上海博迅实业有限公司医疗设备厂)、ZF-6型三用紫外分析仪(上海嘉鹏科技有限公司)、Ultrashied 400MHz Plus核磁共振仪(瑞士 Bruker公司)、API 4000LC-MS/MS质谱仪(德国布鲁克道尔顿公司)
实施例1
以3,4-O-碳酸酯半乳烯糖与对甲苯硫酚为例进行实验条件优化，具体如下：
注:除另外说明，所有试验采用0.1mmol半乳烯糖与0.2mmol对甲苯硫酚，10mol％钴催化剂，20mol％单齿膦配体(或10mol％双齿膦配体)在2mL溶剂中100℃下Schlenk管反应；分离产率；区域选择性与立体选择性由核磁氢谱测得>20:1。XantPhos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，DPPB:1,4-双(二苯基膦)丁烷，DPPF:1,1'-双(二苯基膦)二茂铁。
反应条件筛选试验表明，采用四氟硼化钴水合物催化剂、Xantphos配体在不同的溶剂中反应情况各不相同(entries 1-4)，采用Co(BF4)2催化剂，Xantphos配体在二氯甲烷与四氢呋喃等溶剂中能得到较低产率3-硫-1-烯糖(entries 1-2)，当采用DMSO作为溶剂时，没有目标反应产物(entry 3)，乙腈作为溶剂产率最高可达81％(entry 4)。然后本发明添加15％mol 锌粉发现产率可以提高至92％(entry 5)。继续筛选不同的催化剂(entries6-9)发现Co(BF4)2仍然是最优催化剂，然后对不同的配体进行了筛选(entries 10-13)，确定最优条件为(entry 5, 以Co(BF4)2为催化剂、Xantphos作为膦配体、锌粉为添加剂在乙腈为反应溶剂中100℃反应。且化合物2的构型已经通过高分辨率质谱，核磁共振氢谱、碳谱和二维谱确证。
在上述路线的情况下，本发明采用3,4-O-碳酸酯半乳烯糖为原料制备4-羟基-3硫-1- 烯糖的技术路线：
将四氟硼化钴水合物Co(BF4)2·6H2O，3.4mg,0.01mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos,5.8mg,0.010mmol)，锌粉(0.01mmol)和3,4-O-碳酸酯半乳烯糖1(0.1 mmol)加入2mL的乙腈和硫醇/酚(对甲苯硫酚)(0.2mmol)。100摄氏度搅拌，TLC检测反应进程，当烯糖原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得4-羟基-3-对甲基苯硫基-1-烯糖(收率为92％)。
实施例2
将四氟硼化钴水合物Co(BF4)2·6H2O(3.4mg,0.01mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽 (Xantphos,5.8mg,0.010mmol)，锌粉(0.01mmol)和3,4-O-碳酸酯半乳烯糖1(0.1mmol) 加入2mL的乙腈和间甲苯硫酚(0.2mmol)。100摄氏度搅拌，TLC检测反应进程，当烯糖原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得4-羟基-3-间甲基苯硫基-1-烯糖(收率为 93％)。
实施例3
将四氟硼化钴水合物Co(BF4)2·6H2O，3.4mg,0.01mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(Xantphos,5.8mg,0.010mmol)，锌粉(0.01mmol)和3,4-O-碳酸酯半乳烯糖1(0.1 mmol)加入2mL的乙腈和邻甲苯硫酚(0.2mmol)。100-120摄氏度搅拌，TLC检测反应进程，当烯糖原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得4-羟基-3-邻甲基苯硫基-1-烯糖(收率为89％)。
底物范围
硫醇类：制备步骤参考实施例1
硫酚类：制备步骤参考实施例1
芳杂环类：制备步骤参考实施例1
波谱数据
(2R,3S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(p-tolylthio)-3,4-dihydro-2H-pyran-3-ol. (2)
1H NMR(400MHz,CDCl3)δ7.68(ddt,J＝9.4,6.7,1.6Hz,4H),7.49–7.38(m,6H),7.35– 7.30(m,2H),7.11(d,J＝7.8Hz,2H),6.56(dd,J＝6.0,1.2Hz,1H),4.91(ddd,J＝5.9,5.1,1.8Hz, 1H),4.21(t,J＝4.6Hz,1H),4.14–4.08(m,1H),4.02(dd,J＝10.9,5.2Hz,1H),3.91(dd,J＝10.9,4.0 Hz,1H),3.67–3.60(m,1H),3.14(d,J＝5.2 Hz,1H),2.34(s,3H),1.04(s,9H).
13C NMR(101 MHz,CDCl3)δ146.06,137.54,135.68,135.55,132.68,132.41,132.06,130.43, 129.92,129.90,127.82,127.78,97.82,71.76,68.38,64.54,45.53,26.73,21.09,19.12.
(2R,3S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(m-tolylthio)-3,4-dihydro-2H-pyran-3-ol (3)
1H NMR(400 MHz,CDCl3)δ7.74–7.63(m,4H),7.47–7.36(m,6H),7.24–7.17(m,3H),7.12–7.03(m,1H),6.57(dd,J＝6.1,1.2 Hz,1H),4.92(ddd,J＝6.0,5.1,1.8 Hz,1H),4.21 (t,J＝4.5 Hz,1H),4.15–4.08(m,1H),4.03(dd,J＝10.9,5.0 Hz,1H),3.92(dd,J＝10.9,3.9 Hz,1H),3.76–3.62(m,1H),3.25(d,J＝5.0 Hz,1H),2.32(s,3H),1.04(s,9H).
13C NMR(101 MHz,CDCl3)δ146.22,139.05,135.73,135.60,134.04,132.67,132.39,131.78, 130.00,129.98,129.05,128.19,128.15,127.89,127.85,97.69,71.80,68.64,64.70,44.98,26.77, 21.39,19.16.
(2R,3S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(o-tolylthio)-3,4-dihydro-2H-pyran-3-ol
1H NMR(400 MHz,CDCl3)δ7.72–7.66(m,3H),7.46–7.34(m,8H),7.23–7.15(m,3H),6.64–6.54(m,1H),4.92(ddd,J＝6.2,5.1,1.8 Hz,1H),4.25(t,J＝4.4 Hz,1H),4.09(dd,J ＝4.8,2.3 Hz,1H),4.04(dd,J＝11.0,4.9 Hz,1H),3.93(dd,J＝11.0,3.9 Hz,1H),3.68(dd,J＝5.3, 1.5 Hz,1H),3.30(d,J＝4.9 Hz,1H),2.39(s,3H),1.03(s,9H).
13C NMR(101 MHz,CDCl3)δ146.25,138.82,135.72,135.57,133.64,132.65,132.34,130.62, 130.59,129.98,127.87,127.84,127.10,126.68,97.60,71.92,68.63,64.86,44.02,26.75,20.71, 19.15.
Claims (3)
1.一种3-硫-1-烯糖类化合物的合成方法，其特征在于，包括如下步骤：将催化剂、配体和半乳烯糖加入到乙腈及硫醇/酚中，加入锌粉，100-120摄氏度下搅拌反应，TLC检测反应进程，当半乳烯糖原料完全消失后，终止反应，即可得到3-硫-1-烯糖，反应式如下：
所述的硫醇/酚的结构式为R2-SH，其中R2的结构式选自羧酸酯亚甲基、苄基、烷基、苯基、2-嘧啶基、2-苯并噁唑、咪唑基中的任意一种；R1选自C1-C18烷基、苄基、苯基、三苯基甲基，吡啶基、苯甲酰基，吡啶甲酰基，喹啉甲酰基中的任意一种，所述的催化剂选自CoCl2、CoBr2、Co(acac)2、Co(PPh3)2Cl2、或Co(BF4)2·6H2O中的任意一种；
所述的配体为Xantphos、DPPB、DPPF、PPh3、或P(Cy)3中的任意一种。
2.根据权利要求1所述的3-硫-1-烯糖类化合物的合成方法，其特征在于，催化剂、配体、半乳烯糖、硫醇/酚的摩尔比为0.01-0.05：0.005-0.03：0.5-1：1-4。
3.根据权利要求1所述的3-硫-1-烯糖类化合物的合成方法，其特征在于，锌粉的添加量为半乳烯糖质量的0.1-1倍。
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