Mild, orthogonal solid-phase peptide synthesis: use of N alpha-dithiasuccinoyl (Dts) amino acids and N-(iso-propyldithio)carbonylproline, together with p-alkoxybenzyl ester anchoring linkages.
Mild, orthogonal solid-phase peptide synthesis: use of N alpha-dithiasuccinoyl (Dts) amino acids and N-(iso-propyldithio)carbonylproline, together with p-alkoxybenzyl ester anchoring linkages.
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温和、正交的固相肽合成：使用 N α-二硫代琥珀酰 (Dts) 氨基酸和 N-(异丙基二硫代)羰基脯氨酸，以及对烷氧基苄基酯锚定键。
DOI：
10.1111/j.1399-3011.1987.tb03327.x
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
Barany,G
中科院分区：
文献类型：
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作者：
Albericio,F;Barany,G
在4-二甲基氨基吡啶（0.1当量）存在下，通过使用N，N '-二环己基碳二亚胺或1-（3-二甲基氨基-丙基）-3-乙基碳二亚胺盐酸盐，将几种N α-二硫代琥珀酰基（Dts）氨基酸（1）酯化而不进行外消旋化，生成2，4，5-三氯苯基4′-羟甲基苯氧基乙酸酯（10）或相应的丙酸酯（11）。纯化所得柄衍生物（8，9），然后使用含有1-羟基苯并三唑（0.1 M）的N，N-二甲基甲酰胺作为溶剂，通过偶联定量连接到氨甲基载体上。该方法有利于Dts-氨基酸asp-烷氧基苄基酯的锚定，其可以在25° C下通过三氟乙酸-二氯甲烷（1：1）以良好的产率裂解。模型实验建立了定量硫解去除，（>99.8%）的Dts组发生在（i）β-巯基乙醇（0.5 M）-N，N-二异丙基乙胺（0.5M）的二氯甲烷溶液，2次2 min;（0.5M）-N-甲基吗啉（0.5M）在二氯甲烷中的溶液，2次2 min;和（iii）N-甲基巯基乙酰胺（0.5M）-1-羟基苯并三唑（0.1M）在N，N-二甲基甲酰胺中，2次2 min。还定义了Dts官能团对亲核试剂的敏感性，包括证明叔胺催化的由Dts-二肽基单元形成乙内酰脲，但是在与肽合成相关的适当条件下完全避免了来自这些过程的副反应。利用这些观察结果设计了高产率和纯度的许多模型肽的有效的、无外消旋化的固相合成，包括L-亮氨酰-L-丙氨酰甘氨酰-L-缬氨酸、H-Gly 6-瓦尔-OH、H-Met-Ala-Gly-OH、甲硫氨酸-脑啡肽和缓激肽。
SeveralNα‐dithiasuccinoyl (Dts) amino acids (1) have been esterified without race‐mization by use of eitherN,N'‐dicyclohexylcarbodiimide or 1‐(3‐dimethylamino‐propyl)‐3‐ethylcarbodiimide hydrochloride, each in the presence of 4‐dimethylaminopyridine (0.1 equiv.), to 2, 4, 5‐trichlorophenyl 4′‐hydroxymethylphenoxyacetate (10) or the corresponding propionate (11). The resultant handle derivatives (8,9) were purified and then quantitatively attached onto aminomethyl supports by couplings using as solventN,N‐dimethylformamide containing 1‐hydroxybenzotriazole (0.1 M). This methodology facilitates anchoring of Dts‐amino acids asp‐alkoxybenzyl esters, which can be cleaved in good yields by trifluoroacetic acid‐dichloromethane (1:1) at 25°. Model experiments established that quantitative thiolytic removal (>99.8%) of the Dts group occurs with (i) β‐mercaptoethanol (0.5M)‐N,N‐diisopropylethylamine (0.5M) in dichloromethane, 2 times 2min; (ii)N‐methylmercaptoacetamide (0.5M)‐N‐methylmorpholine (0.5M) in dichloromethane, 2 times 2min; and (iii)N‐methylmercaptoacetamide (0.5M)‐1‐hydroxybenzotriazole (0.1M) inN,N‐dimethylformamide, 2 times 2 min. The susceptibility of the Dts functionality to nucleophiles was also defined, including demonstration of tertiary amine‐catalyzed hydantoin formation from Dts‐dipeptidyl units, but side reactions from these processes are entirely avoided under appropriate conditions relevant to peptide synthesis. These observations were exploited to devise efficient, racemization‐free solid‐phase syntheses of a number of model peptides in high yields and purities, including L‐leucyl‐L‐alanylglycyl‐L‐valine, H‐Gly6‐Val‐OH, H‐Met‐Ala‐Gly‐OH, methionine‐enkephalin, and bradykinin.