Synthesis of Homochiral Tris(2-alkyl-2-aminoethyl)amine Derivatives from Chiral α-Amino Aldehydes and Their Application in the Synthesis of Water Soluble Chelators

A novel synthesis of 3-fold symmetric, homochiral tris(2-alkyl-2-aminoethyl)amine (TREN) derivatives is presented. The synthesis is general in scope, starting from readily prepared chiral α-amino aldehydes. The optical purity of the N-BOC protected derivatives of tris(2-methyl-2-aminoethyl)amine and tris(2-hydroxymethyl-2-aminoethyl)amine has been ascertained by polarimetry and chiral NMR chemical shift experiments. An X-ray diffraction study of the l-alanine derivative (tris(2-methyl-2-aminoethyl)amine·3 HCl, l-Ala3-TREN) is presented: crystals grown from ether diffusion into methanol are cubic, space group P213 with unit cell dimensions a = 11.4807(2) Å, V = 1513.23(4) Å3, and Z = 4. Attachment of the triserine derived backbone tris(2-hydroxymethyl-2-aminoethyl)amine (l-Ser3-TREN) to three 3-hydroxy-1-methyl-2(1H)-pyridinonate (3,2-HOPO) moieties, followed by complexation with Gd(III) gives the complex Gd(l-Ser3-TREN-Me-3,2-HOPO)(H2O)2, which is more water soluble than the parent Gd(TREN-Me-3,2-HOPO)(H2O)2 and a promising candidate for magnetic resonance imaging (MRI) applications. Crystals of the chiral ferric complex Fe(l-Ser3-TREN-Me-3,2-HOPO) grown from ether/methanol are orthorhombic, space group P212121, with unit cell dimensions a = 13.6290(2) Å, b = 18.6117(3) Å, c = 30.6789(3) Å, V = 7782.0(2) Å3, and Z = 8. The solution conformation of the ferric complex has been investigated by circular dichroism spectroscopy. The coordination chemistry of this new ligand and its iron(III) and gadolinium(III) complexes has been studied by potentiometric and spectrophotometric methods. Compared to the protonation constants of previously studied polydentate 3,2-HOPO-4-carboxamide ligands, the sum of protonation constants (log β014) of l-Ser3-TREN-Me-3,2-HOPO (24.78) is more acidic by 1.13 log units than the parent TREN-Me-3,2-HOPO. The formation constants for the iron(III) and gadolinium(III) complexes have been evaluated by spectrophotometric pH titration to be (log K) 26.3(1) and 17.2(2), respectively.