A Facile Synthesis of N-Carboxyanhydrides and Poly(α-amino acid) Using Di-tert-butyltricarbonate
A Facile Synthesis of N-Carboxyanhydrides and Poly(α-amino acid) Using Di-tert-butyltricarbonate
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使用三碳酸二叔丁酯轻松合成 N-羧酸酐和聚（α-氨基酸）
DOI：
10.1021/ma0498464
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
T. Endo
中科院分区：
文献类型：
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作者：
A. Nagai;Daisuke Sato;Junichi Ishikawa;Bungo Ochiai;Hiroto Kudo;T. Endo
氨基酸和多肽的化学在结构解析和合成具有重要生物学功能的寡肽和多肽中占有重要地位。由于最近发酵和有机合成技术的显著进步，我们现在可以以较低的价格获得光学纯的氨基酸。因此，氨基酸和一些寡肽被广泛用于药物、食品、有机合成中的手性来源以及化学和生物方法中的聚合物。由于合成的高相对分子质量的多肽可以作为研究蛋白质物理、化学和生物学性质的模型，因此人们提出了各种各样的多肽合成方法。2-7多肽的化学合成方法可分为两种。第一种是顺序缩合，包括固相合成，提供具有高度调控序列的多肽。4这些多肽已被广泛应用于生物和医药领域，尽管这种方法需要苛刻的工艺，不适合大规模生产。第二种是活性氨基酸衍生物的缩聚和R-氨基酸酸酐(NCA)的开环聚合6，7，得到含有一种氨基酸连接的多肽，这种多肽很容易产生高分子量的多肽。这些多肽被认为是生物和工业领域的重要材料。NCA的开环聚合比缩聚更具优势，因为开环聚合是一种链状聚合，能够提供具有精确拓扑结构(如嵌段和接枝聚合物)和可控结构的多肽。NCA的起始原料一般是由含有光气或三光气的氨基酸制备的，这些氨基酸具有很高的毒性。8反应生成氯化氢，使制备纯NCA变得困难，而副产物氨基酸盐酸盐不受污染。为了解决这些问题，我们选择了二叔丁基三碳酸酯(DBTC)8，9来代替光气(见支持信息)。已经有报道称，DBTC能够以伯胺10和R，ω-异氰酸醇为原料，以氨基醇为原料，方便地合成多异氰酸酯。11我们还报道了用邻苯二甲酸二丁酯一锅法合成了一种L酪氨酸基聚氨酯。在此，我们描述了(1)由R-氨基酸和DBTC合成NCA的简便方法，以及(2)以氨基酸和DBTC为脱水剂的一锅法合成多(氨基酸)。我们首先尝试了以丁二酸丁二醇酯和邻苯二甲酸二丁酯为原料合成γ-苄基-L-谷氨酸-N-羧酸酐(方案1；表1，运行1)。在60℃下，将BLG加入到DBTC(1.1当量)的四氢呋喃(THF)(0.1M)干溶液中，反应温度60℃，反应开始时混合物为非均相溶液，反应2 h后，混合物在CHCl_3溶液中2252.5 cm~(-1)处观察到较强的异氰酸酯红外吸收峰，4 h后吸收峰完全消失，在1851.3 cm~(-1)和1781.9 cm~(-1)处观察到新的红外峰归属于N-羧酸酐中的羰基结构。所得混合物用旋转蒸发器浓缩，残留物用干燥的正己烷洗涤，然后从混合溶剂(四氢呋喃和正己烷)中重结晶，得到高产率的无色固体BLG-NCA。以类似的方式，NCA可以由几种R-氨基酸制备，例如L-丙氨酸、L-亮氨酸和L-苯丙氨酸(表1，运行2-4)。13尽管BLG给出了相应的…
The chemistry of amino acids and peptides is important in the structural elucidation and synthesis of oligoand polypeptides with useful biological function. 1 We can now obtain optically pure amino acids for low prices due to recent remarkable improvements in the technology in fermentation and organic synthesis. Consequently, amino acids and some oligopeptides are now widely used for drug, food, chiral sources in organic synthesis, and polymers from chemical and biological methods. Because synthetic polypeptides with high molecular weight can be models for the general study of physical, chemical, and biological properties of proteins, a wide variety of methods for polypeptides synthesis have been proposed. 2-7 Chemical synthetic methods for polypeptides can be divided into two methods. The first one is sequential condensation including solidphase synthesis that afford polypeptides with highly regulated sequences. 4 These polypeptides have been widely applied in the field of biological and medicinal areas, although this method requires demanding processes and is not suitable for mass production. The second one is polycondensation5 of activated amino acid derivatives and ring-opening polymerization6, 7 of R-amino acid anhydrides (NCAs) that affords polypeptides comprising linkage of one kind of amino acids, which can easily produce high molecular weight polypeptides. These polypeptides are regarded as important materials in biological and industrial areas. Ring-opening polymerization of NCAs is advantageous over the polycondensation because ring-opening polymerization, which is a chain polymerization, is capable of providing polypeptides with precise topology (eg, block and graft polymers) and controlled architecture. The starting materials NCAs have been generally prepared from amino acids with phosgene or triphosgene, which are highly toxic. 8 The reaction generates hydrogen chloride that makes preparation of pure NCAs without contamination of amino acid hydrochloride salts as byproducts difficult. To solve these troubles, we selected di-tert-butyltricarbonate (DBTC) 8, 9 instead of phosgene (see Supporting Information). DBTC has been already reported to enable facile syntheses of multiisocyanate from primary amines10 and R, ω-isocyanato alcohol from amino alcohol. 11 We have also reported a one-pot synthesis of an L-tyrosine-based polyurethane by using the DBTC method. 12 Herein, we describe (1) a facile synthesis of NCAs from R-amino acids and DBTC and (2) a one-pot synthesis of poly (amino acid) from an amino acid and DBTC as a dehydrating agent. We first tried to prepare γ-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA) from BLG and DBTC (Scheme 1; Table 1, run 1). BLG was added to a solution of DBTC (1.1 equiv) in dry tetrahydrofuran (THF)(0.1 M) at 60 C. Although the starting reaction mixture was heterogeneous, the mixture changed to a homogeneous solution after 2 h. Strong IR aborption assignable to the isocyanate was observed at 2252.5 cm-1 in CHCl3 solution of the mixture after 2 h. After 4 h, this absorption completely disappeared, and a new IR aborption assignable to the carbonyl moieties in N-carboxyanhydride was observed at 1851.3 and 1781.9 cm-1. The resulting mixture was concentrated by a rotary evaporator, and residual mass was washed with dry n-hexane, followed by recrystallization from a mixed solvent (THF and n-hexane) to obtain a colorless solid, BLG-NCA, in high yield. In a similar fashion, NCAs could be prepared from several R-amino acids such as L-alanine, L-leucine, and L-phenylalanine (Table 1, runs 2-4). 13 Although BLG gave the corresponding …