title: Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-γ-carboxyglutamic acid.
abstract: 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.
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Glenn P A
authors.initials: GP
authors.lastname: Yap
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
mesh_terms: D003300:Copper / Q000737:chemistry*; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry; D018698:Glutamic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry*; D012545:Schiff Bases / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D005449:Fluorenes; D008024:Ligands; D009942:Organometallic Compounds; D012545:Schiff Bases; D018698:Glutamic Acid; D003300:Copper