Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
J Org Chem. 2011 Mar 18;76(6):1513-20. doi: 10.1021/jo101940k. Epub 2011 Feb 3.
L-γ-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-α-Fmoc-L-γ-carboxyglutamic acid γ,γ'-tert-butyl ester (Fmoc-Gla(O(t)Bu)(2)-OH), a suitably protected analogue for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structure-based design was inspired by the blue copper protein rusticyanin. The five-coordinate complex is formed by Shiff base formation between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl)aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the α-carbon of the glycine portion of the complex occurs in a diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex, the asymmetric synthesis of Fmoc-Gla(O(t)Bu)(2)-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield.
L-γ-羧基谷氨酸（Gla）是一种不常见的氨基酸，它能与矿物质表面和金属离子紧密结合。在此，我们报告了 N-α-Fmoc-L-γ-羧基谷氨酸 γ,γ'-叔丁酯（Fmoc-Gla(O(t)Bu)(2)-OH）的合成，这是一种适合基于 Fmoc 的固相肽合成的保护类似物。该残基使用一种新型手性 Cu(II)配合物合成，其结构设计灵感来自蓝色铜蛋白锈蓝蛋白。在铜的存在下，通过甘氨酸和新型配体（S）-2-（N-（2-甲硫基）苄基脯氨酰基）氨基苯并酮之间的席夫碱形成五元配合物。二烯丙基马来酸二甲酯与配合物中甘氨酸部分的α-碳发生非对映选择性迈克尔加成。所得（S，S）-配合物非对映异构体可以通过色谱法轻松纯化。金属配合物分解后进行 Fmoc 保护，得到手性纯氨基酸。使用这种新型手性配合物，从硫代水杨酸经九步反应以 14.5%的总收率完成了 Fmoc-Gla(O(t)Bu)(2)-OH 的不对称合成。
