兼容生物大分子的硫亚胺脱氢Chan-Lam偶联反应研究

硫亚胺作为亚砜的氮杂类似物，在化学与生物学领域受到越来越多的关注。在生物大分子中，特别是肽和蛋白质上引入硫亚胺（S=N）结构，将赋予其独特的化学物理性质与新颖的生物活性。然而，N-芳基硫亚胺的传统合成方法，需要强氧化剂或者强碱性条件，因此底物范围受限，限制了硫亚胺在药物化学以及化学生物学中的进一步研究应用。本论文受亚砜配体与金属配位过程中内壳单电子转移机制的启发，发展了一种氧化还原中性的硫亚胺脱氢Chan-Lam偶联方法，以较高收率和良好的底物兼容性构建了一系列N-芳基硫亚胺类化合物。温和的反应条件和优异的化学选择性，使得该方法被成功应用于复杂肽分子的后期官能团修饰以及蛋白的化学标记中，实现了在肽分子与蛋白水平上构建S=N键。主要研究内容如下：

在无外加氧化剂条件下，实现了NH-二芳基硫亚胺与芳基硼酸的脱氢Chan-Lam偶联反应。反应条件温和，无需外加酸、碱和配体，具有良好的官能团兼容性。值得一提的是，以酪氨酸硼酸衍生物为底物时，也能以较高的化学选择性得到相应的偶联产物，为后续肽分子修饰奠定了基础。通过一系列控制实验、波谱表征以及计算化学方法，对这一氧化还原中性的硫亚胺脱氢Chan-Lam偶联反应机理进行了进一步的研究。通过电子顺磁共振波谱分析与紫外可见光谱分析，证明了在无外加氧化剂的条件下，NH-硫亚胺可以有效促进一价铜到二价铜的氧化。通过气相色谱分析与气体质谱检测，证实了H2是反应体系的主要副产物之一，H2中的氢原子分别来自于NH-硫亚胺与溶剂。结合实验与理论计算，确定了H2产生的反应途径，即：NH-硫亚胺与一价铜配位，通过内壳单电子转移过程形成含有硫亚胺自由基阴离子的二价铜过渡态，随后铜原子插入N-H键，经三元环过渡态产生含有三价铜的铜氢中间体，后者通过四元环过渡态从异丙醇溶剂中攫取氢正离子释放出 H2。该反应方法可以作为传统Chan-Lam偶联方法的有效补充，避免了外加氧化剂导致的副反应以及底物受限。

受到氧化还原中性以及酪氨酸硼酸衍生物成功兼容的启发，将铜催化硫亚胺脱氢Chan-Lam偶联方法拓展至肽分子的修饰中。通过对含酪氨酸硼酸衍生物的二肽底物的考察发现，反应表现出良好的底物普适性与化学选择性，可以很好地兼容氨基酸残基中的-OH、-SH、-CONH2以及吲哚-NH官能团等传统Chan-Lam偶联反应中的活性基团。该反应对于含酪氨酸硼酸衍生物的功能性三肽分子同样适用，以68%-96%的收率获得了对应的偶联产物。对于四肽以上肽链更长、结构更为复杂的肽分子，包括两种内源性肽分子endomorphin-1、met-enkephalin，以及外源性的七肽分子deltorphin I，通过该偶联策略也能够成功实现相应肽分子的硫亚胺化修饰。氧化还原中性的反应特点，使得这一新发展的偶联策略克服了传统Chan-Lam偶联应用于肽分子修饰中存在的化学选择性问题，表现出了良好的氨基酸兼容性，成功地实现了对多种功能性肽分子的硫亚胺化修饰。

在广泛的肽底物兼容性基础上，进一步探索将这一温和高效的偶联反应方法发展为一种有效的蛋白质硫亚胺化标记策略。为了保证蛋白质结构与功能的完整性，如何在接近生理学条件中高选择性地实现蛋白质的硫亚胺化标记，是该标记策略的主要化学挑战。选取了分子量为33 kDa、具有312个氨基酸残基的Halotag 7作为模型蛋白，经过一系列的条件优化后，最终克服了有机溶剂的限制，在以pH 7.4的PBS缓冲溶液为主要反应介质的反应体系中，以43%的收率生成目标蛋白Protein 7，实现了对Halotag 7的硫亚胺化修饰。IV型胶原蛋白内硫亚胺键的共价交联是保证基质膜结构完整性的关键因素。因此，在蛋白水平上研究硫亚胺键的稳定性具有重要的参考意义。通过免疫印迹实验，首次对蛋白质中的硫亚胺键在生理相关条件下的化学稳定性进行了考察。结果表明，蛋白质中硫亚胺键具有一定的氧化条件耐受性，但对酸、碱、还原性条件以及培养基条件较为敏感。在众多考察的生理学相关因素中，高温可以在较短时间内对硫亚胺键产生最为显著的破坏作用。

Sulfilimines, the aza-analogues of sulfoxides, have drawn increasing attention in the fields of chemistry and biology. Derivatization of biomacromolecules, especially peptides and proteins with this S(IV)-derived motif could endow them with novel chemophysical properties and biological activities. However, their further uptake in medicinal chemistry as well as chemical biology was hampered since the traditional synthetic methods of N-aryl sulfilimines require strong oxidants or alkaline conditions, which result in the limited substrate scope. In this dissertation, a redox-neutral Chan-Lam coupling reaction of free sulfilimines was developed inspired by the classic electron-transfer process of sulfoxide ligand isomerization while binding to metal complexes. It permits facile access to a myriad of NAr-diaryl sulfilimines and even allows the synthesis of sulfilimine-modified peptides and protein under biomolecule-compatible conditions. The main research contents are as follows:

Copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids has been developed with excellent chemoselectivity and broad substrate compatibility. Moreover, a tyrosine-derived boronic acid was also compatible with the transformation, which laid the foundation for the subsequent peptide modification. The mechanism of the redox-neutral sulfilimine dehydrogenative coupling reaction was further investigated through a series of control experiments, spectroscopic characterization, and computational investigation. Cu(II) complex was characterized by EPR and UV-Vis spectra while mixing with NH-sulfilimine, supporting that the free sulfilimines could facilitate the oxidation of Cu(I) to Cu(II) in the absence of external oxidants.  Besides, based on gas chromatography analysis and gas mass spectrometry analysis of the gaseous byproducts in the reaction system with headspace injection, H2 was one of the major by-products of the reaction system, and the hydrogen atoms in H2 originated from NH-sulfilimine and solvent, respectively. A combined experimental and computational study reveals the copper hydride pathway of H2 generation: CuBr binds to NH-sulfilimines to yield Cu(II) intermediate featuring a radical anion NH-sulfilimine ligand via an inner-sphere electron transfer process. Subsequently, an insertion of Cu(II) into the N-H bond of the sulfilimine leads to the formation of three-membered transition state. Cu(II)-facilitated homolysis of O–H bond of iPrOH occurs to give a formal Cu(III) hydride species, which can release the hydrogen gas via a feasible four-membered transition state. The protocol described herein represents an appealing alternative to classic oxidative C-N coupling strategy, enabling greater substrate generality, and eliminating byproducts from oxidants.

Encouraged by redox-neutral reaction conditions and the excellent chemoselectivity with tyrosine-derived substrate, the suitability of the newly devised copper-catalyzed Chan-Lam coupling to afford sulfilimine-modified peptides was investigated next. The introduction of second amino acid attached to the tyrosine-based boronic acid exerted negligible effect to the outcome of this protocol, favoring C-N bond formation of sulfilimine N-H bonds over C-O, C-S, or C-N bond formation of hydroxyls O-H bonds, thiol S-H bonds, amide N-H bonds, or indole N-H bonds. The Tyr(B(OH)2) derivative of tripeptides were also well-suited to the method, providing the corresponding products in 68%-96% yields. Remarkably, the chemistry was well accommodated with more complex tetrapeptides and pentapeptides, including two endogenous opioid receptor agonists endomorphin-1 and met-enkephalin, and an exogenous opioid receptor agonist deltorphin I. The redox-neutral characteristics enables this newly developed coupling strategy to overcome the chemoselectivity problems when the traditional Chan-Lam coupling was applied to the peptide modifications, highlighting good amino acid compatibility and various bioactive peptides were successfully sulfilimine-modified.

Encouraged by the broad tolerance to different peptides, the copper-catalyzed Chan-Lam coupling of free sulfilimines was developed as a selective protein bioconjugation method. To ensure the structural and functional integrity of proteins, how to achieve highly selective sulfilimine-labeling of proteins under physiological conditions is the main chemical challenge of this labeling strategy. Halotag 7, the 33 kDa monomeric protein, was selected as a model protein substrate for this study. After a series of condition optimization, the target protein 7 was finally obtained in 43% yield using a PBS buffer solution (pH 7.4) as the main reaction medium. The sulfilimine covalent crosslink in collagen IV serves as a key reinforcement that stabilizes basement membranes. Therefore, the stability of sulfilimines in the context of proteins stands as a significant yet unsolved question. The chemical stability of the sulfilimine motif in protein structures under various physiologically relevant conditions was firstly investigated by Western blots in this thesis. The results show that the sulfilimine bond in protein 7 was relatively stable under oxidative conditions. Nevertheless, the S=N bond is sensitive to acidic, basic, reductive, or under the treatment of Dulbecco’s Modified Eagle Medium (DMEM). Among all the factors examined, high temperature caused the most degradation of the sulfilimine motif even in a very short period of time.

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