CN111978278B - 一类2,3-不饱和糖氧苷类化合物的合成方法 - Google Patents
一类2,3-不饱和糖氧苷类化合物的合成方法 Download PDFInfo
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- CN111978278B CN111978278B CN202010832236.7A CN202010832236A CN111978278B CN 111978278 B CN111978278 B CN 111978278B CN 202010832236 A CN202010832236 A CN 202010832236A CN 111978278 B CN111978278 B CN 111978278B
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- carbonate
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- -1 glycoside compounds Chemical class 0.000 title claims abstract description 31
- 229930182470 glycoside Natural products 0.000 title claims abstract description 27
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000003446 ligand Substances 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 13
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 8
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 claims abstract description 6
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims abstract description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004327 boric acid Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 3
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- HMFHBZSHGGEWLO-HWQSCIPKSA-N L-arabinofuranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@H]1O HMFHBZSHGGEWLO-HWQSCIPKSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
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- 239000002994 raw material Substances 0.000 description 7
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000003147 glycosyl group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
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- 239000000758 substrate Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- KFXUHRXGLWUOJT-UHFFFAOYSA-N (4-phenoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OC1=CC=CC=C1 KFXUHRXGLWUOJT-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 2
- 238000003584 Ferrier rearrangement reaction Methods 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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Abstract
本发明提供一种2,3‑不饱和糖氧苷类化合物的合成方法，包括如下步骤：在催化剂、配体、碱和糖受体中加入有机溶剂及碳酸酯阿拉伯烯糖，室温下搅拌反应，TLC检测反应进程，当碳酸酯阿拉伯烯糖原料完全消失后，终止反应，即可得到2,3‑不饱和糖氧苷，所述的糖受体为有机硼酸结构式为R2‑B(OH)2，其中R2的结构式包括亚甲基羧酸酯、苄基、烷基、单糖、多糖、肽、蛋白质、苯基、取代苯基、芳香基、五元或六元杂环基中的任意一种。本发明采用高活性的碳酸酯烯糖供体开发出了一种在室温非无水无氧条件高立体选择性的氧糖苷化方法。
Description
技术领域
本发明主要关于一种2,3-不饱和糖氧苷类化合物的合成方法。属于化学合成技术领域。
背景技术
糖类的研究对化学与生命科学发展均具有重要意义，开发高效立体选择性的糖苷化方法是糖化学的核心领域。糖苷类化合物根据与端基碳所连原子的种类，可分为氧苷、碳苷和氮苷等。这些分子广泛存在于天然产物与药物之中，例如，氧苷哇巴因(Ouabain)是 Na+-K+-ATP酶抑制剂可用于心血管疾病，治疗碳苷恩格列净(Empagliflozin)是临床抗糖尿病药物，氮苷蝴蝶霉素(Rebeccamycin)是一种新型抗肿瘤剂。由于糖类自身结构复杂，具有多个活泼羟基以及手性中心，形成的糖苷键又具有α,β两种立体构型，至今未能开发出通用的简便糖苷化方法。
开发新型的糖供体以达到高立体选择性是糖苷化研究的主要策略之一。经典糖苷化方法通常选用饱和糖供体，通过异头效应、邻基参与、分子内糖基配体转移(IAD)等方法来选择性构建新的糖苷键。国外糖化学家Schmidt R.R.,Ito Y.,Demchenko A.V.,BoonsG.J., Crich D.,Davis B.G.,Bennett C.S.,Liu X.-W.等均曾采用此策略进行糖苷化的研究。我国科学家俞飚、叶新山、万谦、杨劲松、孙建松等都在饱和糖供体进行高效糖苷化领域做了非常重要的贡献。不饱和糖(烯糖)供体糖苷化反应起步相对较晚，研究较少，直到近年尤其是近二十年随着过渡金属化学的发展，烯糖在导向型糖苷化反应方面快速发展。烯糖供体相对饱和糖供体有几个优点：1)双键可以与过渡金属配位，在导向立体选择性方面具有很大潜力；2)所需的保护基减少；3)新形成的双键易被官能团化。同时由于邻基参与和IAD效应的缺失，选择性控制存在一定的挑战，可采用烯糖氧糖苷化的方法主要有Ferrier重排、 Tsuji-Trost反应。而Ferrier重排仅能形成α选择性为主的氧苷，Tsuji-Trost型反应由于烯糖本身活性较低难以与过渡金属配位形成金属配合物中间体，糖苷化反应难以发生，更重要的是几乎所有的氧糖苷化反应都需要在无水无氧的条件下进行操作，反应条件较苛刻、操作繁琐，成本较高。
发明内容
针对上述技术问题，本发明采用高活性的碳酸酯烯糖供体开发出了一种在室温非无水无氧条件高立体选择性的氧糖苷化方法。
一种2,3-不饱和糖氧苷类化合物的合成方法，包括如下步骤：在钯催化剂、膦配体、碱和有机硼酸作为糖受体中加入有机溶剂及碳酸酯阿拉伯烯糖，室温下搅拌反应，TLC检测反应进程，当碳酸酯阿拉伯烯糖原料完全消失后，终止反应，即可得到2,3-不饱和糖氧苷，所述的反应式如下：
所述的有机硼酸糖受体的结构式为R2-B(OH)2，其中R2的结构式包括亚甲基羧酸酯、苄基、烷基、单糖、多糖、肽、蛋白质、苯基、取代苯基、芳香基、五元或六元杂环基中的任意一种。
目前一般糖受体采用醇或者酚为糖受体，若敞口反应则与空气中的水有竞争反应，糖苷化反应获得氧苷的较为困难或者产率很低，而本发明采用对空气不敏感的有机硼酸为氧糖苷化反应糖受体则巧妙地避免了这一点，因此操作方便且产率较高。
所述的五元或六元杂环基包括2-嘧啶基、2-苯并噁唑、或咪唑基中的任意一种。
所述的PG包括氢、烷基、硅氧基、烷氧基、C1-C18烷氧基、苄氧基、苯氧基，三苯基甲氧基，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Pd(acac)2、Pd(OAc)2、PdCl2、Pd(PPh3)2Cl2、Pd(TFA)2、 Pd(CH3CN)4(BF4)2、Pd(C5HF6O2)2、Pd(CN)2、(C2H5CO2)2Pd、PdCl2(cod)、Pd(OTf)2(dippp)、 Whitecatalyst中的任意一种。
所述的配体包括DPPB、DPPF、XantPhos、DPEPhos、P(Cy)3、PPh3、PMe3、 JackiePhos、JohnPhos、Sphos、XPhos、tBuXPhos、EvanPhos、RuPhos、BINAP中任意一种。
所述的碱包括LiOH、NaOH、KOH、Ca(OH)2、Li2CO3、Na2CO3、CS2CO3、 tBuOK、NaOMe、Et3N、DBU、吡啶、二乙胺、烟碱、胍中任意一种。
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、碱、碳酸酯阿拉伯烯糖、硼酸的摩尔比为(0.01-0.1):(0.01-0.2):(0.1- 2):1:(1-4)。
采用本发明的工艺得到的产品包括如下：
中的任意一种。
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
醋酸钯(北京百灵威科技有限公司)、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(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
以碳酸酯阿拉伯烯糖为例，采取不同催化剂、配体及碱的优化实验方案，具体如下：
注:所有试验采用0.1mmol碳酸酯阿拉伯烯糖与0.2mmol对苯氧基苯硼酸，5mol％Pd催化剂，10mol％膦配体(14-18加碱20mol％)在2mL溶剂中室温下搅拌反应；分离产率；立体选择性有核磁氢谱测得>＝30:1。DPEPhos:双(2-二苯基膦)苯醚，DPPB:1,4-双(二苯基膦)丁烷，DPPF:1,1'-双(二苯基膦)二茂铁。
本发明的技术方案对反应条件进行了筛选优化。在THF做溶剂的条件下，首先对催化剂进行筛选(entries 1-4)。发现当使用零价钯作为催化剂时，反应效果不好甚至没有反应 (entries 1-2)。然后用二价钯催化剂进行试验(entries 3-5)，实验结果表明，当用White catalyst和Pd(OAc)2作为催化剂时，12的产率可以达到82％(entry 3，5)。接下来，对反应溶剂进行了优化(entries 5-8)，优化结果表明，在CH3CN作为溶剂的条件下，反应效果最好，12的产率可以达到86％(entry 8)。为了能够得到32b，本发明尝试向反应体系中添加配体，看能否能实现32b的高效选择性合成(entries 10-13)。实验结果表明，在配体存在的情况下，并无32b的产生。后来本发明又尝试向反应体系中添加无机碱，以外欣喜的是，实验表明，在CS2CO3存在的条件下，32b的产率为42％(entry 14)，为了进一步提高产率，本发明对配体又进行了一次筛选优化(entries 15-18)，试验表明，在DPPB，CS2CO3共同存在的条件下，32b的产率可以达到82％。尝试其他不同的碱发现，叔丁醇钾(entry 19) 与氢氧化锂(entry 20)也可以以良好的产率获得32b。
综述实验结果，得到了阿拉伯糖芳基碳苷最优的反应条件为在Pd(OAc)2作为催化剂，CH3CN作为溶剂时反应效果最好；阿拉伯糖芳基氧苷最优的反应条件为在Pd(OAc)2作为催化剂，DPPB作为配体，CS2CO3作为添加剂，CH3CN作为溶剂时反应效果最好。
在上述路线的情况下，本发明还以3,4-O-碳酸酯阿拉伯烯糖为原料制备了β-对苯氧基苯氧基-4-羟基-2,3-不饱和氧苷，技术路线如下：
将醋酸钯(Pd(OAc)2，1.1mg，0.005mmol)，1,4-双(二苯基磷)丁烷(DPPB,2.1mg,0.005 mmol)，碳酸铯(0.02mmol)和糖受体(对苯氧基苯硼酸)(0.2mmol)加入2mL的二氯甲烷和3,4-O-碳酸酯阿拉伯烯糖1(0.1mmol)。室温搅拌，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-2,3-不饱和氧苷(收率为82％)。
实施例2
本发明还以3,4-O-碳酸酯阿拉伯烯糖为原料在Pd(OAc)2作为催化剂，DPPB作为配体， CS2CO3作为添加剂，CH3CN作为溶剂时制备β-对甲苯基-4-羟基-2,3-不饱和氧苷的技术路线：
将醋酸钯(Pd(OAc)2，1.1mg,0.005mmol),1,4-双(二苯基磷)丁烷(DPPB,2.1mg,0.005 mmol)，碳酸铯(0.02mmol)和糖受体(对甲苯硼酸)(0.2mmol)加入2mL的二氯甲烷和3,4-O-碳酸酯阿拉伯烯糖1(0.1mmol)。室温搅拌，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β-对甲苯基-4-羟基-2,3-不饱和氧苷(收率为82％)。
实施例3
本发明还以3,4-O-碳酸酯阿拉伯烯糖为原料在Pd(OAc)2作为催化剂，DPPB作为配体， CS2CO3作为添加剂，CH3CN作为溶剂时制备β-对甲苯基-4-羟基-2,3-不饱和氧苷的技术路线：
将醋酸钯(Pd(OAc)2，1.1mg,0.005mmol),1,4-双(二苯基磷)丁烷(DPPB,2.1mg,0.005 mmol)，碳酸铯(0.02mmol)和糖受体(间甲苯硼酸)(0.2mmol)加入2mL的二氯甲烷和3,4-O-碳酸酯阿拉伯烯糖1(0.1mmol)。室温搅拌，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β-间甲苯基-4-羟基-2,3-不饱和氧苷(收率为81％)。
底物范围
醇类与糖类底物制备氧苷参考实施例1的条件17
酚类底物制备氧苷参考实施例1的条件17
波谱数据
(3R,6R)-6-(4-phenoxyphenoxy)-3,6-dihydro-2H-pyran-3-ol
1H NMR(400MHz,CDCl3)δ7.31(dd,J＝8.6,7.4Hz,2H),7.12–7.02(m,3H),7.00–6.91(m,4H),6.16(ddd,J＝10.2,3.5,1.2Hz,1H),5.94(ddd,J＝10.2,2.6,1.9Hz,1H),5.58(d,J ＝2.8Hz,1H),4.35(s,1H),3.92(dd,J＝10.9,5.6Hz,1H),3.79(dd,J＝10.9,8.8Hz,1H),1.69(d, J＝8.4Hz,1H)；
13C NMR(101MHz,CDCl3)δ158.1,153.3,151.6,134.2,129.7,126.6,122.7,120.6,118.1,117.9, 93.2,63.9,63.0.
(3R,6R)-6-(p-tolyloxy)-3,6-dihydro-2H-pyran-3-ol
1H NMR(400MHz,CDCl3)δ7.10(d,J＝8.4Hz,2H),7.05–6.85(m,2H),6.15(dd,J＝10.2,2.3Hz,1H),5.94(dd,J＝10.3,4.4Hz,1H),5.59(d,J＝2.7Hz,1H),4.34(s,1H),3.90(dd,J ＝10.9,5.5Hz,1H),3.78(dd,J＝11.0,8.7Hz,1H),2.30(s,3H)；
13C NMR(101MHz,CDCl3)δ154.9,134.0,131.6,129.9,126.7,116.6,92.8,63.8,63.0,20.6.
(3R,6R)-6-(m-tolyloxy)-3,6-dihydro-2H-pyran-3-ol
1H NMR(400MHz,CDCl3)δ7.22–7.13(m,1H),6.93–6.81(m,3H),6.15(dd,J＝10.2,1.2Hz,1H),5.93(d,J＝10.3Hz,1H),5.62(d,J＝2.7Hz,1H),4.34(s,1H),3.91(ddd,J＝10.9, 5.5,1.1Hz,1H),3.77(dd,J＝10.9,8.7Hz,1H),2.34(s,3H).
13C NMR(101 MHz,CDCl3)δ157.1,139.6,134.0,129.2,126.6,123.0,117.3,113.6,92.5,63.9, 63.0,21.5.
Claims (3)
1.一种2,3-不饱和糖氧苷类化合物的合成方法，其特征在于，包括如下步骤：在催化剂Pd(OAc)2、配体、碱和糖受体有机硼酸中加入有机溶剂及碳酸酯阿拉伯烯糖，室温下搅拌反应，TLC检测反应进程，当碳酸酯阿拉伯烯糖原料完全消失后，终止反应，即可得到2,3-不饱和糖氧苷，配体为DPPB、DPPF、或P(Cy)3中的任意一种；所述的碱为LiOH、CS2CO3、或tBuOK；
所述的反应式如下：
所述的糖受体的结构式为有机硼酸R2-B(OH)2，其中R2的结构式为苄基、单糖、苯基、2-嘧啶基、2-苯并噁唑、或咪唑基中的任意一种。
2.根据权利要求1所述的2,3-不饱和糖氧苷类化合物的合成方法，其特征在于，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。
3.根据权利要求1所述的2,3-不饱和糖氧苷类化合物的合成方法，其特征在于，催化剂、配体、碱、碳酸酯阿拉伯烯糖、糖受体有机硼酸的摩尔比为的摩尔比为(0.01-0.1):(0.01-0.2):(0.1-2):1:(1-4)。
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