High-Yield Synthesis of the Enterobactin Trilactone and Evaluation of Derivative Siderophore Analogs1

A novel one-step synthesis of the macrocyclic triserine trilactone scaffold of the siderophore enterobactin, which eliminates the β-lactonization step of N-tritylserine, is presented. The cyclization reaction is based on a stannoxane template and leads to an overall yield of ∼50%. This enables the practical functionalization of the trilactone by attaching chelating groups other than catecholamides. The conformational stability of the trilactone ring has been examined by high-resolution X-ray diffraction studies of the N-trityl intermediate: crystals grown from methylene chloride:methanol are orthorhombic, space group P212121 with unit cell dimensions a = 9.2495(5) Å, b = 11.3584(1) Å, c = 48.945(1) Å, V = 5142.1(2) Å3, and Z = 4. A hydroxypyridinonate analog of enterobactin, N,N‘,N‘‘-tris[(3-hydroxy-1-methyl-2-oxo-(1H-pyridinyl)carbonyl]-4-cyclotriseryl trilactone (hopobactin), has been prepared by attachment of three 3-hydroxy-1-methyl-2(1H)-pyridinonate (3,2-HOPO) moieties to the triserine trilactone. This ligand represents the first enterobactin analog that retains the trilactone scaffold, but employs chelates other than catecholamides. Crystals of the chiral ferric complex grown from DMF:diethyl ether are monoclinic, space group P21, with unit cell dimensions a = 13.0366(9) Å, b = 22.632(2) Å, c = 27.130(2) Å, b = 100.926(1)°, V = 7860(1) Å3, and Z = 8. The Δ configuration of enterobactin metal complexes is also enforced in those of hopobactin and persists in aqueous or methanolic solution, as demonstrated by circular dichroism. The ferric hopobactin complex is the first reported chiral complex of hydroxypyridinonate ligands. The solution coordination chemistry of this new ligand and its iron(III) and iron(II) complexes have been studied by means of 1H NMR, potentiometric, spectrophotometric, and voltammetric methods. The average protonation constant of the hopobactin free ligand (log K av = 6.1) is typical of other 3-hydroxy-1-methyl-2-oxo-1H-pyridin-4-carboxamide ligands. The stability constants of the iron(III) complex formed with hopobactin (log β110 = 26.4) and with the tris(2-aminoethyl)amine-based analog, TRENHOPO, (log β110 = 26.7) are of the same order of magnitude, unlike the catecholamide-based species, where enterobactin (log β110 = 49) is 6 orders of magnitude more stable than TRENCAM (log β110 = 43.6). The stability enhancement reflects the specific predisposition by the triserine scaffold of the catecholamide binding units. In spite of