Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in the Synthesis of Fmoc-L-γ-carboxyglutamic Acid

被引:14
|
作者
Smith, Daniel J. [1 ,2 ]
Yap, Glenn P. A. [2 ]
Kelley, James A. [1 ]
Schneider, Joel P. [1 ]
机构
[1] Natl Canc Inst Frederick, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA
[2] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA
来源
JOURNAL OF ORGANIC CHEMISTRY | 2011年 / 76卷 / 06期
关键词
MICHAEL ADDITION-REACTIONS; ALPHA-AMINO-ACIDS; SUBSTITUTED GLUTAMIC ACIDS; EFFICIENT ASYMMETRIC-SYNTHESIS; VIRTUALLY COMPLETE CONTROL; STEM-CELL DIFFERENTIATION; NI-II COMPLEXES; NUCLEOPHILIC GLYCINE; FACE DIASTEREOSELECTIVITY; PYROGLUTAMIC ACIDS;
D O I
10.1021/jo101940k
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
L-gamma-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-alpha-Fmoc-L-gamma-carboxyglutamic acid gamma,gamma'-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)benzylproly)aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the alpha-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.
引用
收藏
页码:1513 / 1520
页数:8
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