Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.

The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields.

New methodology for the preparation of 3-hydroxy-2-pyridinone (3,2-HOPO) chelators and extractants. Part 2. Reactions of alcohols, phenols, and thiols with an electrophilic 3,2-HOPO reagent().

The reactions of the electrophilic iminium ester mesylate salt 1 with alcohols, phenols and thiols has been investigated. In the presence of base, thiols, phenols and thiophenol react with 1 to give the corresponding ether linked HOPO derivatives in good yields. However, the ring opening of salt 1 with alcohols could only be accomplished efficiently using a large excess of the alcohol in the presence of methanesulfonic acid at 80°C.

New methodology for the preparation of 3-hydroxy-2-pyridinone (3,2-HOPO) chelators - Reaction of amines with a novel electrophilic 3,2-HOPO precursor.

The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21.