Iron(III)-templated macrolactonization of trihydroxamate siderophores

Abstract

A method was developed to synthesize macrocyclic trihydroxamate siderophores using optimized Yamaguchi macrolactonization conditions. The natural ability of siderophores to bind iron(III) was exploited to template the reactions and allowed for rapid reaction rates, high product conversions, and the formation of large macrolactone rings up to 35 atoms. An X-ray structure of a 33-membered macrolactone siderophore-Fe(III) complex is presented.

Figure 1

Structures of linear and macrocyclic trihydroxamate siderophores from the ferrioxamine family.

Figure 2

Design for Fe(III)-templation to bring the hydroxyl and carboxyl groups into closer proximity.

Figure 3

X-ray structure of the danoxamine macrolactone-Fe(III) complex, 5b, displayed with 50% probability ellipsoids.

Scheme 2

Scaled up macrolactonization of danoxamine, 5a, and deferration to give desferridanoxamine macrolactone 4.