Macrocyclic hydroxamic acids coordinate Fe(III) with high affinity as part of siderophore-mediated bacterial iron acquisition. Trimeric hydroxamic acid macrocycles, such as desferrioxamine E (DFOE), are prevalent in nature, with fewer dimeric macrocycles identified, including putrebactin (pbH₂), avaroferrin (avH₂), bisucaberin (bsH₂) and alcaligin (alH₂). This work used metal-templated synthesis (MTS) to pre-assemble complexes between one equivalent of Fe(III) and two equivalents of 4-((4-aminobutyl)(hydroxy)amino)-4-oxobutanoic acid (BBH) or 4-((5-aminopentyl)(hydroxy)amino)-4-oxobutanoic acid (PBH). Following peptide coupling, the respective Fe(III) complexes of pbH₂ or bsH₂ were formed, which analysed by LC-MS under acidic pH as [Fe(pb)]⁺ ([M]⁺, m/z_obs 426.1) or [Fe(bs)]⁺ ([M]⁺, m/z_obs 454.2). The mixed-ligand 1:1:1 Fe(III):BBH:PBH system furnished [Fe(pb)]⁺ and [Fe(bs)]⁺, together with chimeric [Fe(av)]⁺ ([M]⁺, m/z_obs 440.2). The deviation from the expected 1:2:1 distribution of [Fe(pb)]⁺:[Fe(av)]⁺:[Fe(bs)]⁺ to 1:3.2:1.6 suggested the MTS-mediated formation of dimeric macrocycles could be influenced by steric effects in the pre-complex and/or cavity size, as governed by the monomer. 21-Membered avH₂ defined the lower boundary of the optimal architecture. Mixed-ligand MTS between Fe(III):PBH-d₄:ret-PBH at 1:1.5:1.5, where ret-PBH = 3-(6-amino-N-hydroxyhexanamido)propanoic acid, gave four Fe(III)-loaded trimeric hydroxamic acid macrocycles in a distribution of 1.0:3.0:2.9:1.1 that closely matched the expected distribution 1:3:3:1 for a system without any kinetic and/or thermodynamic bias. Apo-macrocycles pbH₂, avH₂ and bsH₂ were produced upon incubation with diethylenetriaminepentaacetic acid (DTPA) and co-eluted with a biosynthetic mixture of the native macrocycles. The work has demonstrated the utility of single- and mixed-ligand MTS for producing a variety of homo- and heteroleptic dimeric hydroxamic acid macrocycles as Fe(III) complexes and free ligands.

大环异羟肟酸作为铁载体介导的细菌铁捕获的一部分，以高亲和力配位Fe（III）。三聚体异羟肟酸大环化合物，例如去铁胺X（E）（DFOE），在自然界中很普遍，发现的二聚体大环化合物较少，包括腐霉菌素（pbH ₂），阿伐铁蛋白（avH ₂），比沙卡伯林（bsH ₂）和alcaligin（alH ₂）。这项工作使用金属模板合成（MTS）来预组装一当量的Fe（III）与两当量的4-（（4-氨基丁基）（羟基）氨基）-4-氧代丁酸（BBH）或4 -（（5-氨基戊基）（羟基）氨基）-4-氧代丁酸（PBH）。肽偶联后，分别为pbH ₂或bsH _2的Fe（III）复合物形成，通过LC-MS在酸性pH下分析为[Fe（pb）] ⁺（[M] ⁺，m / z _obs 426.1）或[Fe（bs）] ⁺（[M] ⁺，m / z _obs 454.2）。混合配体1：1：1 Fe（III）：BBH：PBH系统提供[Fe（pb）] ⁺和[Fe（bs）] ⁺以及嵌合[Fe（av）] ⁺（[M] ⁺，m / z _obs 440.2）。与[Fe（pb）] ⁺：[Fe（av）] ⁺：[Fe（bs）] ^+的1：2：1预期分布的偏差到1：3.2：1.6表明，MTS介导的二聚体大环化合物的形成可能受预配合物和/或空腔尺寸（受单体支配）的空间效应影响。21成员的avH ₂定义了最佳架构的下边界。Fe（III）：PBH- d ₄：ret -PBH在1：1.5：1.5之间的混合配体MTS ，其中ret -PBH = 3-（6-氨基-N-羟基己酰胺基）丙酸，得到四个Fe（III）负载的三聚异羟肟酸大环化合物，其分布为1.0：3.0：2.9：1.1，与系统的预期分布为1：3：3：1紧密匹配，而没有任何动力学和/或热力学偏差。载脂蛋白大环pbH ₂，avH ₂和bsH ₂在与二亚乙基三胺五乙酸（DTPA）孵育后，生成天然产物，并与天然大环化合物的生物合成混合物共洗脱。这项工作证明了单配体和混合配体的MTS可以作为Fe（III）配合物和游离配体生产各种均配和杂配的二聚异羟肟酸大环化合物。