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 异青霉素N-合成酶(IPNS)和半胱氨酸双加氧酶(CDO)。前者提供了我们唯一的β来源- 内酰胺类抗生素，后者已知可以防止癌症肿瘤的转移和神经疾病。 人们对这些反应的机理知之甚少，对这些反应的了解将有助于 细菌尚未产生抗药性的新型抗癌药物和抗生素的合成。很少有井- 表征了FeIII-O2·-的化合物已有报道，只有两个化合物在配位中含有硫酸盐 球体。我们的小组报道了第一个也是唯一一个RS-FeIII-O2·-能够裂解强C-H键的例子 与IPNS裂解的半胱氨酸β-C-H键相当。在此提出的工作目标将是确定 配基约束能否将我们的RS-FeIII-O2·-从IPNS反应途径改变为IPNS反应途径 CDO。我们将把β-氢结合到我们的脂肪族硫酸盐配体中，并确定分子内 βC-H键发生断裂，β-Dh看看这是否稳定了FeIII-O2·-，如果是的话，确定 动力学同位素效应，为分子内β-C-H键断裂提供额外的支持。我们将决定 反式硫酸盐是否影响我们的RS-FeIII-O2·-关于C-H键断裂的效力 探索我们的混合醇盐/硫酸盐连接的FeII络合物的氧化学。我们将使用穆斯堡尔 光谱和光谱电化学为质子耦合电子的参与提供证据 在我们假定的高价O=(R)S-FeIV=O到相应的O=(R)S-FeIII-OH的转化中的转移 从Pourbai x(pH对E_1/2)图的斜率得到FeIIIO-H键强度。我们还将研究 氧化还原失活的Lewis酸性阳离子和质子对我们的结晶学表征能力的影响 顺式RS-FeIV=O裂解强C-H键，并通过合成确定硫酸盐如何影响这一反应活性 相应的顺式RO-FeIV=O化合物和用光谱检测pH依赖的氧化还原电位。 电化学和比较O-H键强度，从Pourbai x的斜率(pH与E_1/2)获得 顺式RO-FeIII-OH与顺式RS-FeIII-OH的关系图。我们将在配体支架中插入一个亚甲基 我们的结晶学表征为顺式RS-FeIV=O，以确定配体限制是否阻止 分子内氧原子转移。最后，我们将确定𝛑-之间的协同交互是否 供体硫酸盐和接受𝛑的CO配体促进氢酶(H2-ase)促进H2的产生和H2 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.