纳米碳酸钾脱除Fmoc保护基的新方法
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摘要
Fmoc是一种常用的氨基保护基,传统的脱除方法是通过加入二级胺与之作用来实现。针对方法中存在的成本较高、使用的过量二级胺不易回收以及污染环境等缺点,建立了利用新型无机碱纳米碳酸钾非均相脱除Fmoc保护基的新方法。采用湿法研磨方法,将普通碳酸钾制成粒径为64nm的纳米碳酸钾,以Fmoc保护的L-苯丙氨酸的脱保护反应为Model反应,确定了最佳反应条件:反应溶剂为无水乙醇,Fmoc-L-Phe-OBn与纳米碳酸钾物质的量比为1︰2,反应温度为25℃,高产率得到了相应的游离氨基化合物,进一步研究了新方法的适用范围,对7个Fmoc保护的氨基酸和二肽的底物进行了测试。结果表明,产率均在98%以上,且纳米碳酸钾能够回收再利用,在5次之内的活性几乎没有变化。新方法具有操作简单、成本低、污染小、碳酸钾可回收利用的优点,对多肽的合成及脱保护研究有重要的参考价值。
Fmoc is usually used as an amino-protecting group.The traditional removal method is realized by using a secondary amine.However,this method has some shortcomings including high cost,difficult recycle of excess secondary amine and environmental pollution.The paper reports a novel heterogeneous deprotection method of Fmoc group using a new inorganic base,namely,nano-potassium carbonate.Nano-potassium carbonate with average particle size 64 nm is prepared using wet grinding method.The deprotection of Fmoc-Phe-OBn is preformed as a Model reaction.The optimum conditions are that reaction solvent is absolute ethanol,molar ratio of Fmoc-L-Phe-OBn to nano-K_2CO_3 is 1︰2,and reaction temperature is 25 ℃.The corresponding free amino compound is obtained with high yield.To further explore the scope and limitations of this method,seven substrates including Fmoc-anmino acids and dipeptides are examined.All the yields are above 98%.The nano-K_2CO_3 could beregenarated and reused for 5 times without loss of its reactive activity.This method has the advantages of simple operation,low cost,small pollution and recyclable potassium carbonate,and has important reference value for the research on the synthesis and deprotection of polypeptides.
Fmoc is usually used as an amino-protecting group.The traditional removal method is realized by using a secondary amine.However,this method has some shortcomings including high cost,difficult recycle of excess secondary amine and environmental pollution.The paper reports a novel heterogeneous deprotection method of Fmoc group using a new inorganic base,namely,nano-potassium carbonate.Nano-potassium carbonate with average particle size 64 nm is prepared using wet grinding method.The deprotection of Fmoc-Phe-OBn is preformed as a Model reaction.The optimum conditions are that reaction solvent is absolute ethanol,molar ratio of Fmoc-L-Phe-OBn to nano-K_2CO_3 is 1︰2,and reaction temperature is 25 ℃.The corresponding free amino compound is obtained with high yield.To further explore the scope and limitations of this method,seven substrates including Fmoc-anmino acids and dipeptides are examined.All the yields are above 98%.The nano-K_2CO_3 could beregenarated and reused for 5 times without loss of its reactive activity.This method has the advantages of simple operation,low cost,small pollution and recyclable potassium carbonate,and has important reference value for the research on the synthesis and deprotection of polypeptides.
引文
[1]WUTS P G M,GREENE T W.Greene′s Protective Groups in Organic Synthesis[M].[S.l.]:Wiley-Interscience,2007.
[2]CARPINO L A,HAN G Y.9-fluorenylmethoxycarbonyl function,a new base-sensitive amino-protecting group[J].J Am Chem Soc,1970,92(19):5748-5749.
[3]ISIDROLLOBET A,ALVAREZ M,ALBERICIO F.Amino acid-protecting groups[J].Chemical Reviews,2009,109(6):2455.
[4]杜秀敏.Fmoc系列保护氨基酸的制备研究[D].南京:南京工业大学,2004.DU Xiumin.Preparation of Fmoc Series Protected Amino Acids[D].Nanjing:Nanjing University of Technology,2004.
[5]赵萍萍,徐大刚,廖晓全,等.保护氨基酸Fmoc-His(Trt)-OH的合成方法优化[J].化学世界,2008,49(9):549-552.ZHAO Pingping,XU Dagang,LIAO Xiaoquan,et al.The optimization of sythesis of amino acid Fmoc-His(Trt)-OH[J].Chemistry World,2008,49(9):549-552.
[6]NARDI M,CANO N H,COSTANZO P,et al.Aqueous MW eco-friendly protocol for amino group protection[J].Rsc Advances,2015,5(24):18751-18760.
[7]MANSOURI R,AOUF Z,LAKROUT S,et al.A greener,efficient and catalyst-free ultrasonic-assisted protocol for the N-Fmoc protectionof amines[J].Journal of the Brazilian Chemical Society,2016,27(3):94-106.
[8]GREENE T W,WUTS P G M.Protecting Groups in Organic Synthesis[M].[S.l.]:[s.n.],1999.
[9]PEARSON A J,ROUSH W R.Handbook of Reagents for Organic Synthesis,Activating Agents and Protecting Groups[M].New York:John Wiley&Sons,1999.
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[12]DIGIOIA M L,COSTANZO P,DENINO A,et al.Simple and efficient Fmoc removal in ionic liquid[J].Rsc Advances,2017,7(58):36482-36491.
[13]CARPINO L A,HAN G Y.9-fluorenylmethoxycarbonyl amino-protecting group[J].Journal of Organic Chemistry,2002,37(22):4218.
[14]UEKI M,AMEMIYA M.Removal of 9-fluorenylmethyloxycarbonyl(Fmoc)group with tetrabutylammonium fluoride[J].Tetrahedron Letters,1987,28(52):6617-6620.
[15]SCHMIDT U,MUNDINGER K,MANGOLD R,et al.Lavendomycin:Total synthesis and assignment of configuration[J].Journal of the Chemical Society Chemical Communications,1990,18(18):1216-1219.
[16]李腾.饮用水源中痕量二级胺检测方法及其应用的研究[D].长沙:中南林业科技大学,2012.LI Teng.Study on the Detection of Trace Secondary Amines in Drinking Water Sources and Its Application[D].Changsha:Central South University of Forestry and Technology,2012.
[17]杨亚男.碱性氨基酸盐活化碳酸钾溶液吸收CO2的动力学研究[D].石家庄:河北科技大学,2016.YANG Yanan.Study on Kinetics of CO2 Absorption by Alkaline Amino Acids in Potassium Carbonate Solutions[D].Shijiazhuang:Hebei University of Science and Technology,2016.
[18]肖元化.多孔SnO2纳米材料与CNTs基复合纳米材料的制备及其气敏性能研究[D].长沙:中南大学,2010.XIAO Yuanhua.Preparation and gas sensitivity of porous SnO2nanocomposites and CNTs-based Nanocomposites[D].Changsha:Central South University,2010.
[19]ZHONG C,YANG B,JIANG X,et al.Current progress of nanomaterials in molecularly imprinted electrochemical sensing[J].Critical Reviews in Analytical Chemistry,2017(16):7947-7954.
[20]赵辉.几种金属氧化物纳米催化材料的制备及催化性能、机理研究[D].无锡:江南大学,2015.ZHAO Hui.Preparation of Several Metal Oxide Nano Catalysts and Their Catalytic Performance and Mechanism[D].Wuxi:Jiangnan University,2015.
[21]LI Junzhang,FAN Shiming,SUN Fengxia,et al.Nano-K2CO3:Preparation,characterization and evaluation of reactive activities[J].Rsc Advances,2016,6(3):1865-1869.
[22]李军章.纳米碳酸盐的制备及其化学反应行为的研究[D].天津:河北工业大学,2013.LI Junzhang.Preparation of Nanocarbonate and Study on Its Chemical Reaction Behavior[D].Tianjin:Hebei University of Technology,2013.
[23]邹明静,王娜.基于纳米金等离子体共振光散射法测定阿米卡星[J].河北工业科技,2017,34(1):18-22.ZOU Mingjing,WANG Na.Determination of amikacin based on nano gold plasma pesonance light scattering[J].Hebei Journal of Industrial Science and Technology,2017,34(1):18-22.
[2]CARPINO L A,HAN G Y.9-fluorenylmethoxycarbonyl function,a new base-sensitive amino-protecting group[J].J Am Chem Soc,1970,92(19):5748-5749.
[3]ISIDROLLOBET A,ALVAREZ M,ALBERICIO F.Amino acid-protecting groups[J].Chemical Reviews,2009,109(6):2455.
[4]杜秀敏.Fmoc系列保护氨基酸的制备研究[D].南京:南京工业大学,2004.DU Xiumin.Preparation of Fmoc Series Protected Amino Acids[D].Nanjing:Nanjing University of Technology,2004.
[5]赵萍萍,徐大刚,廖晓全,等.保护氨基酸Fmoc-His(Trt)-OH的合成方法优化[J].化学世界,2008,49(9):549-552.ZHAO Pingping,XU Dagang,LIAO Xiaoquan,et al.The optimization of sythesis of amino acid Fmoc-His(Trt)-OH[J].Chemistry World,2008,49(9):549-552.
[6]NARDI M,CANO N H,COSTANZO P,et al.Aqueous MW eco-friendly protocol for amino group protection[J].Rsc Advances,2015,5(24):18751-18760.
[7]MANSOURI R,AOUF Z,LAKROUT S,et al.A greener,efficient and catalyst-free ultrasonic-assisted protocol for the N-Fmoc protectionof amines[J].Journal of the Brazilian Chemical Society,2016,27(3):94-106.
[8]GREENE T W,WUTS P G M.Protecting Groups in Organic Synthesis[M].[S.l.]:[s.n.],1999.
[9]PEARSON A J,ROUSH W R.Handbook of Reagents for Organic Synthesis,Activating Agents and Protecting Groups[M].New York:John Wiley&Sons,1999.
[10]KOCIENSKI P J.Synthesis alerts 10/05[J].Synthesis,2005(10):1718-1725.
[11]李鑫,朱颐申,应汉杰.侧链羟基氨基酸保护工艺优化研究[C]//第一届全国化学工程与生物化工年会.南京:南京工业大学出版社,2004:646-647.
[12]DIGIOIA M L,COSTANZO P,DENINO A,et al.Simple and efficient Fmoc removal in ionic liquid[J].Rsc Advances,2017,7(58):36482-36491.
[13]CARPINO L A,HAN G Y.9-fluorenylmethoxycarbonyl amino-protecting group[J].Journal of Organic Chemistry,2002,37(22):4218.
[14]UEKI M,AMEMIYA M.Removal of 9-fluorenylmethyloxycarbonyl(Fmoc)group with tetrabutylammonium fluoride[J].Tetrahedron Letters,1987,28(52):6617-6620.
[15]SCHMIDT U,MUNDINGER K,MANGOLD R,et al.Lavendomycin:Total synthesis and assignment of configuration[J].Journal of the Chemical Society Chemical Communications,1990,18(18):1216-1219.
[16]李腾.饮用水源中痕量二级胺检测方法及其应用的研究[D].长沙:中南林业科技大学,2012.LI Teng.Study on the Detection of Trace Secondary Amines in Drinking Water Sources and Its Application[D].Changsha:Central South University of Forestry and Technology,2012.
[17]杨亚男.碱性氨基酸盐活化碳酸钾溶液吸收CO2的动力学研究[D].石家庄:河北科技大学,2016.YANG Yanan.Study on Kinetics of CO2 Absorption by Alkaline Amino Acids in Potassium Carbonate Solutions[D].Shijiazhuang:Hebei University of Science and Technology,2016.
[18]肖元化.多孔SnO2纳米材料与CNTs基复合纳米材料的制备及其气敏性能研究[D].长沙:中南大学,2010.XIAO Yuanhua.Preparation and gas sensitivity of porous SnO2nanocomposites and CNTs-based Nanocomposites[D].Changsha:Central South University,2010.
[19]ZHONG C,YANG B,JIANG X,et al.Current progress of nanomaterials in molecularly imprinted electrochemical sensing[J].Critical Reviews in Analytical Chemistry,2017(16):7947-7954.
[20]赵辉.几种金属氧化物纳米催化材料的制备及催化性能、机理研究[D].无锡:江南大学,2015.ZHAO Hui.Preparation of Several Metal Oxide Nano Catalysts and Their Catalytic Performance and Mechanism[D].Wuxi:Jiangnan University,2015.
[21]LI Junzhang,FAN Shiming,SUN Fengxia,et al.Nano-K2CO3:Preparation,characterization and evaluation of reactive activities[J].Rsc Advances,2016,6(3):1865-1869.
[22]李军章.纳米碳酸盐的制备及其化学反应行为的研究[D].天津:河北工业大学,2013.LI Junzhang.Preparation of Nanocarbonate and Study on Its Chemical Reaction Behavior[D].Tianjin:Hebei University of Technology,2013.
[23]邹明静,王娜.基于纳米金等离子体共振光散射法测定阿米卡星[J].河北工业科技,2017,34(1):18-22.ZOU Mingjing,WANG Na.Determination of amikacin based on nano gold plasma pesonance light scattering[J].Hebei Journal of Industrial Science and Technology,2017,34(1):18-22.