一种二肽甜味剂的合成及表征
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摘要
以3-环己基-L-丙氨酸、Boc-L-天冬氨酸-4-苄酯为原料合成二肽L-天冬氨酰-3-环己基-L-丙氨酸-1-甲酯(Ⅰ),以3-羟基-4-甲氧基苯甲醛为原料经过Witting反应、H2还原和DIBAL-H还原三步反应合成3-羟基-4-甲氧基苯丙醛(Ⅱ),然后Ⅰ与Ⅱ在氢气、Pd/C催化作用下进行还原氨化反应,得到目标产物N-[3-(3-羟基-4-甲氧基苯基)丙基]-α-L-天冬氨酰-3-环己基-L-丙氨酸-1-甲酯(Ⅲ),总产率为47%。产物的结构采用IR、~1HNMR、~(13)CNMR和HRMS进行表征,并验证其甜度约为蔗糖的25000倍。合成终产物的最佳工艺条件为:n(Ⅱ)∶n(Ⅰ)=1∶1,Pd/C催化剂用量为反应物总重的10%,体积分数80%的甲醇水溶液为溶剂,反应温度35℃,反应时间20 h。
The dipeptide sweetener, N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl-β-cyclohexyl-Lalanine-1-methylester(Ⅲ) was synthesized from 3-(3-hydroxy-4-methoxyphenyl)propanal(Ⅱ) and dipeptide(Ⅰ) via a reductive amination reaction in the presence of a catalytic amount of palladium-carbon under hydrogen. The total yield was 47%. Compound Ⅱ was prepared from 3-hydroxy-4-methoxybenzaldehyde by Witting reaction, followed by hydrogenation and DIBAL-H reduction. The dipeptide(Ⅰ) was synthesized via a condensation between 3-cyclohexyl-L-alanine and Boc-L-aspartic acid-4-benzyl ester. The structure of product(Ⅲ) was confirmed by IR, ~1 HNMR, ~(13) CNMR and HRMS techniques. It was 25000 times sweeter than sucrose. The optimum reaction conditions for the synthesis of product(Ⅲ) were determined as follows: n(Ⅱ)∶n(Ⅰ)=1∶1, the amount of Pd/C catalyst being 10% of the total weight of reactants, 80%(volume fraction) methanol as solvent, reaction temperature 40 ℃, and reaction time 20 h.
The dipeptide sweetener, N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl-β-cyclohexyl-Lalanine-1-methylester(Ⅲ) was synthesized from 3-(3-hydroxy-4-methoxyphenyl)propanal(Ⅱ) and dipeptide(Ⅰ) via a reductive amination reaction in the presence of a catalytic amount of palladium-carbon under hydrogen. The total yield was 47%. Compound Ⅱ was prepared from 3-hydroxy-4-methoxybenzaldehyde by Witting reaction, followed by hydrogenation and DIBAL-H reduction. The dipeptide(Ⅰ) was synthesized via a condensation between 3-cyclohexyl-L-alanine and Boc-L-aspartic acid-4-benzyl ester. The structure of product(Ⅲ) was confirmed by IR, ~1 HNMR, ~(13) CNMR and HRMS techniques. It was 25000 times sweeter than sucrose. The optimum reaction conditions for the synthesis of product(Ⅲ) were determined as follows: n(Ⅱ)∶n(Ⅰ)=1∶1, the amount of Pd/C catalyst being 10% of the total weight of reactants, 80%(volume fraction) methanol as solvent, reaction temperature 40 ℃, and reaction time 20 h.
引文
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[3]Liu B,Ha M,Meng X Y,et al.Molecular mechanism of speciesdependent sweet taste toward artificial sweeteners[J].The Journal of Neuroscience,2011,31(30):11070-11076.
[4]Nofre C,Tinti J M.Neotame:Discovery,properties,utility[J].Food Chemistry,2000,69(3):245-257.
[5]Prakash I,Corliss G,Ponakala R,et al.Neotame:the next generation sweetener[J].Food Technology,2002,56(7):36-45.
[6]Tanielyan S K,Augusline R L.Synthesis of 3,3-dimethylbutanol and3,3-dimethylbutanal,important intermediates in the synthesis of neotame[J].Topics in Catalysis,2012,55(7):625-630.
[7]Amino Y,Mori K,Tomiyama Y,et al.Development of new,low calorie sweetener:New aspartame derivative[J].ACS Symposium Series,2008,30:463-480.
[8]Hayes J E.Transdisciplinary perspectives on sweetness[J].Chemosensory Perception,2008,1(1):48-57.
[9]Acree T E,Lindley M.Structure-activity relationship and AH-B after40 years[J].ACS Symposium Series,2008,6:96-108.
[10]Garbow J R,Likos J J,Schroeder S A.Structure,dynamics,and stability ofβ-cyclodextrin inclusion complexes of aspartame and neotame[J].Agriculture Food Chemistry,2001,49(4):2053-2060.
[11]Kunari A,Arora S,Choudhary S,et al.Comparative stability of aspartame and neotame in yoghurt[J].International Journal of Dairy Technology,2018,71(1):81-88.
[12]Amino Y,Yuzawa K,Takemoto T,et al.Aspartyl dipeptide ester derivatives and sweeteners:JP3959964B2[P].2007-08-15.
[13]Mori K,Fujita S,Funakoshi N,et al.Process for producing cinnamaldehyde derivatives,use thereof and the like:JP4706161B2[P].2011-06-22.
[14]Amino Y,Yuzawa K,Takemoto T.Novel aspartyl dipeptide ester derivatives and sweeteners:EP1088829A1[P].2001-04-04.
[15]Chattopadhyay S,Raychaudhuri U,Chakraborty R.Artificial sweeteners--Areview[J].Food Science Technology,2014,51(4):611-621.
[16]Otabe A,Fujieda T,Masuyama T.In vitro and in vivo assessment of the mutagenic activity of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester,monohydrate(advantame)[J].Food and Chemical Toxicology,2011,49(1):S30-S34.
[17]Otabe A,Fujieda T,Masuyama T,et al.Advantame-an overview of the toxicity data[J].Food and Chemical Toxicology,2011,49(1):S2-S7.
[18]Prakash I,Wachholder K.Method for the purification N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine-1-methylester:US6784309B2[P].2004-08-31.
[19]Capua A D,Goodman M,Amino Y,et al.Conformation analysis of aspartame-based sweeteners by NMR spectroscopy,molecular dynamics simulations,and X-ray diffraction studies[J].Chem Bio Chem,2006,7(2):377-387.
[20]Tissot M,Phipps R J,Lucas C,et al.Gram-scale enantioselective formal synthesis of morphine through an ortho-para oxidative phenolic coupling strategy[J].Angewandte Chemistry,2014,53(49):13498-13501.
[21]Taylor J E,Daniels D S,Smith A D.Asymmetric NHC-catalyzed redoxα-amination ofα-aroyloxyaldehydes[J].Organic Letters,2013,15(23):6058-6061.
[22]Amino Y,Yuzawa K,Takemono T.Process for producing and purifying aspartame derivative as sweetener:WO2001018034A1[P].2001-03-15.
[23]Gan S F,Yan R A,Li A J.Synthesis of N-[N-3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine-1-methyl ester[J].Science and Technology of Food Industry,2011,32(8):336-338.