Understanding How Thiolates Promote Dioxygen Chemistry

项目摘要 半胱氨酸连接的非血红素铁超氧中间体（RS-FeIII-O2·-）在铁的氧化机制中起关键作用。 异青霉素N-合酶（IPNS）和半胱氨酸双加氧酶（CDO）。前者提供了我们唯一的β- 内酰胺类抗生素，已知后者可预防癌性肿瘤和神经系统疾病的转移。 对这些反应的机理知之甚少，了解这些机理将有助于 合成新的抗癌药物和抗生素，细菌还没有抗药性。很少- 特征FeIII-O2·-化合物已经报道，并且只有两个在配位中包括硫醇盐 球体。我们的小组报道了第一个也是唯一一个能够断裂强C-H键的RS-FeIII-O2·-的例子 与IPNS切割的半胱氨酸β-C-H键相当。本文提出的工作目标是确定 配体约束是否可以用来改变我们的RS-FeIII-O2·-从IPNS的反应途径， 的CDO。我们将把β-氢纳入我们的脂肪族硫醇配体，并确定是否分子内 β C-H键断裂发生，β-氘，看看是否稳定FeIII-O2·-，如果是这样，确定 动力学同位素效应为分子内β-C-H键断裂提供额外支持。我们将确定 反式硫醇盐是否影响我们的RS-FeIII-O2·-在C-H键裂解方面的效力， 探索我们的混合醇盐/硫醇盐连接的Fe II复合物的O2化学。我们将使用穆斯堡尔 光谱和光谱电化学提供证据的参与质子耦合电子 在我们假定的高价O=（R）S-FeIV=O转化为相应的O=（R）S-FeIII-OH的过程中发生转移， 从Pourbaix（pH vs E1/2）图的斜率获得FeIIIO-H键强度。我们亦会研究 氧化还原非活性刘易斯酸性阳离子和质子对我们的晶体学表征的能力的影响 顺式RS-FeIV=O来切割强C-H键，并通过合成硫醇盐来确定硫醇盐如何影响这种反应性。 相应的顺式RO-FeIV=O化合物，并使用光谱法检测pH依赖的氧化还原电位。 电化学和比较O-H键强度，从Pourbaix的斜率（pH值与E1/2）获得 图，对于顺式RO-FeIII-OH相对于顺式RS-FeIII-OH。我们将在配体骨架中插入一个亚甲基， 我们的晶体学表征顺式RS-FeIV=O，以确定配体约束是否阻止 分子内氧原子转移最后，我们将确定是否协同作用之间的相互作用， 提供硫醇盐和吸收CO的配体促进氢化酶（H2-ase）促进H2的产生，𝛑 乳沟

Project Summary Cysteinate-ligated non-heme iron superoxo intermediates (RS-FeIII-O2•–) play a key role in the mechanisms of isopenicillin N-synthase (IPNS) and cysteine dioxygenase (CDO). The former provides our only source of β- lactam antibiotics, and the latter is known to prevent metastases of cancerous tumors and neurological disorders. Very little is known about the mechanisms of these reactions, the understanding of which will facilitate the synthesis of new anticancer drugs and antibiotics to which bacteria are not yet resistant. Very few well- characterized FeIII-O2•– compounds have been reported, and only two include a thiolate in the coordination sphere. Our group reported the first and only example of an RS-FeIII-O2•– capable of cleaving strong C-H bonds on par with cysteine β-C-H bond cleaved by IPNS. The goal of the work proposed herein will be to determine whether ligand constraints can be used to alter the reaction pathway of our RS-FeIII-O2•– from that of IPNS to that of CDO. We will incorporate β-hydrogens into our aliphatic thiolate ligand and determine whether intramolecular β C-H bond cleavage occurs, and β-deuteriums to see if that stabilizes the FeIII-O2•–, and if so, determine the kinetic isotope effect to provide additional support for intramolecular β-C-H bond cleavage. We will determine whether the trans thiolate influences the potency of our RS-FeIII-O2•– with respect to C-H bond cleavage by exploring the O2 chemistry of our mixed alkoxide/thiolate-ligated FeII complex. We will use Mossbauer spectroscopy and spectro-electrochemistry to provide evidence for the involvement of proton coupled electron transfer in the conversion of our putative high valent O=(R)S-FeIV=O to the corresponding O=(R)S-FeIII-OH and obtain the FeIIIO–H bond strength from the slope of the Pourbaix (pH vs E1/2) diagram. We will also examine the effects of redox inactive Lewis acidic cations and protons on the ability of our crystallographically characterized cis RS-FeIV=O to cleave strong C-H bonds, and determine how the thiolate affects this reactivity by synthesizing the corresponding cis RO-FeIV=O compound and examining pH-dependent redox potentials using spectro- electrochemistry and comparing the O–H bond strengths, obtained from the slope of the Pourbaix (pH vs E1/2) diagram, for cis RO-FeIII-OH versus cis RS-FeIII-OH. We will insert a methylene group into the ligand scaffold of our crystallographically characterized cis RS-FeIV=O to determine whether ligand constraints prevent intramolecular oxo atom transfer. Lastly, we will determine whether the synergistic interaction between a 𝛑- donating thiolate and 𝛑-accepting CO ligands facilitates hydrogenase (H2-ase) promoted H2 production and H2 cleavage.