The University of Sydney, School of Medical Sciences (Pharmacology), New South Wales 2006, Australia.
The University of Sydney, School of Medical Sciences (Pharmacology), New South Wales 2006, Australia.
J Inorg Biochem. 2021 Mar;216:111337. doi: 10.1016/j.jinorgbio.2020.111337. Epub 2020 Dec 16.
Dimeric hydroxamic acid macrocycles are a subclass of bacterial siderophores produced for iron acquisition. Limited yields from natural sources provides the impetus to develop synthetic routes to improve access to these compounds, which have potential utility in metal ion binding applications in the environment and medicine. This work has examined the role of metal ions in forming pre-complexes with linear endo-hydroxamic acid (endo-HXA) ligands bearing terminal amine and carboxylic acid groups optimally configured for in situ ring closure reactions. The 1:1 reaction between Fe(III) and the dimeric endo-HXA ligand 5-((5-(5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanamido)pentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH-PPH) (1) formed the pre-complex (PC) [Fe(PP-PP)-PC] with in situ amide coupling generating the macrocycle (MC) [Fe(PP)-MC] and, following Fe(III) removal, the apo-macrocycle 1,13-dihydroxy-1,7,13,19-tetraazacyclotetracosane-2,6,14,18-tetraone (PPH)-MC (2). The 1:2 reaction system between Fe(III) and the monomeric endo-HXA ligand 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH) gave significantly less [Fe(PP)-MC] than the former system, due to the requirement to form two rather than one amide bond(s). The 1:1 Ga(III):1 system yielded [Ga(PP-PP)-PC] and [Ga(PP)-MC]. Neither [Zr(PP-PP)-PC] nor [Zr(PP)-MC] was detected in the 1:1 Zr(IV):1 system. Instead, the Zr(IV) system showed the formation of a 1:2 Zr(IV):1 pre-complex [Zr(PP-PP)-PC], which following in situ amide bond forming chemistry, generated two Zr(IV) macrocyclic complexes with distinct architectures: a dimer-of-dimers complex [Zr((PP))-MC] and an end-to-end macrocycle [Zr(PP)-MC]. The formation of [Fe(PP)-MC], [Ga(PP)-MC] or [Zr((PP))-MC] was confirmed from reconstitution experiments with 2. The work has shown that the choice of metal ion in metal-assisted ring closure reactions directs the assembly of macrocyclic complexes with distinct architectures.
二聚羟肟酸大环是一类细菌铁载体，用于铁的获取。从天然来源获得的有限产量促使人们开发合成途径来提高这些化合物的可及性，这些化合物在环境和医学中的金属离子结合应用中有潜在的用途。这项工作研究了金属离子在与线性内消旋羟肟酸（endo-HXA）配体形成预配合物中的作用，这些配体带有末端胺基和羧酸基，最适合进行原位环合反应。Fe(III)与二聚内消旋 endo-HXA 配体 5-((5-(5-((5-氨基戊基)(羟基)氨基)-5-氧戊基酰胺基)戊基)(羟基)氨基)-5-氧戊酸（PPH-PPH）（1）的 1:1 反应形成预配合物（PC）[Fe(PP-PP)-PC]，其中原位酰胺偶联生成大环（MC）[Fe(PP)-MC]，并在 Fe(III)去除后，生成脱辅基大环 1,13-二羟基-1,7,13,19-四氮杂环二十四烷-2,6,14,18-四酮（PPH）-MC（2）。Fe(III)与单体内消旋羟肟酸配体 5-((5-氨基戊基)(羟基)氨基)-5-氧戊酸（PPH）的 1:2 反应体系产生的[Fe(PP)-MC]明显少于前一个体系，这是由于需要形成两个而不是一个酰胺键。Ga(III):1 系统的 1:1 Ga(III)：1 生成[Ga(PP-PP)-PC]和[Ga(PP)-MC]。在 1:1 Zr(IV):1 系统中未检测到[Zr(PP-PP)-PC]或[Zr(PP)-MC]。相反，Zr(IV)系统显示出 1:1 Zr(IV):1 预配合物[Zr(PP-PP)-PC]的形成，随后进行原位酰胺键形成化学，生成两种具有不同结构的 Zr(IV)大环络合物：二聚体-二聚体络合物[Zr((PP))-MC]和端到端大环络合物[Zr(PP)-MC]。通过与 2 进行重组实验，证实了[Fe(PP)-MC]、[Ga(PP)-MC]或[Zr((PP))-MC]的形成。这项工作表明，在金属辅助的闭环反应中选择金属离子可以指导具有不同结构的大环络合物的组装。
