Photoredox-Catalyzed Reactions for Application in Medicinal Chemistry – A Novel Strategy for Difluoromethylation & Stable S–C(sp2) Linkers for Antibody-Drug Conjugates

本工作的目的是设计两个光氧化还原催化的转换应用于药物化学。将开发用于小分子的二氟甲基化和用于构建稳定的抗体-药物缀合物（ADC）的新策略。偕二氟化合物在药物和农用化学品中无处不在。在过去几年中，报道了许多光氧化还原催化的二氟甲基化，其依赖于用不饱和底物捕获还原产生的二氟甲基自由基（例如，炔、芳烃、烯烃、异腈）。在第一个子项目中，将开发一种补充方法-用1，1-二氟乙烯捕获氧化产生的烷基自由基。这种新的策略将克服以前的限制，使自由基二氟烷基化使用羧酸，醛（通过二氢吡啶），醇（通过碳酸酯）或烷基三氟硼酸酯作为自由基前体。然而，由于1，1-二氟乙烯是气态的并且易于自由基聚合，因此需要合适的替代物。乙烯基硼酸酯，如市售的乙烯基-Bpin，似乎是这方面有前途的候选者。后者与氧化生成的烷基自由基在Selectfluor存在下的反应，随后脱硼/脱硼，应提供一锅法获得所需的二氟烷基化产物。所设计的方法的效用将被证明在设计的前列腺素类似物的合成从市售衍生物的科里内酯。第二个子项目旨在开发用于ADC的新型接头。这种免疫缀合物提供了将药物活性化合物选择性地递送至特定细胞类型的机会，因此理想地适合于癌症治疗中使用的有害细胞毒素。在大多数情况下，接头/细胞毒素单元与抗体的缀合通过半胱氨酸侧链与马来酰亚胺的迈克尔反应完成。然而，由于释放的细胞毒素引起的全身毒性，其可逆性限制了ADC的循环半衰期并降低了治疗窗。在这个项目的过程中，将开发新的连接体，使稳定的S-C（sp2）共轭物的建设通过光氧化还原或镍/光氧化还原双催化。将使用谷胱甘肽作为含半胱氨酸的模型底物，结合苄胺和短寡肽作为细胞毒素占位符来研究反应。然后将优化的条件应用于曲妥珠单抗的功能化，曲妥珠单抗是一种用于靶向乳腺癌细胞的市售抗体。在用寡肽作为细胞毒素占位剂微调反应条件后，将组装由曲妥珠单抗和单甲基澳瑞他汀E作为细胞毒素组成的完整ADC。

The objective of this work is the design of two photoredox-catalyzed transformations for application in medicinal chemistry. New strategies for the difluoromethylation of small molecules and for the construction of stable antibody-drug conjugates (ADCs) will be developed. Geminal difluorides are omnipresent in pharmaceuticals and agrochemicals. In the past years, many photoredox-catalyzed difluoromethylations were reported that rely on trapping of reductively generated difluoromethyl radicals with unsaturated substrates (e.g., alkynes, arenes, alkenes, isocyanides). In the first subproject, a complementary approach will be developed – trapping of oxidatively generated alkyl radicals with 1,1-difluoroethene. This new strategy will overcome previous limitations by enabling a radical difluoroalkylation using carboxylic acids, aldehydes (via dihydropyridines), alcohols (via oxalates) or alkyl trifluoroborates as radical precursors. However, since 1,1-difluoroethene is gaseous and prone to radical polymerization, a suitable surrogate is necessary. Vinylboronates, such as the commercially available vinyl-Bpin, appear to be promising candidates in this respect. Reaction of the latter with oxidatively generated alkyl radicals in the presence of Selectfluor with subsequent deboronation/fluorination should provide a one-pot access to the desired difluoroalkylated products. The utility of the devised method will be demonstrated in the synthesis of designed prostaglandin analogs from commercially available derivatives of Corey lactone. The second subproject aims at developing novel linkers for ADCs. Such immunoconjugates offer the chance to deliver a pharmaceutically active compound selectively to a specific cell type and are hence ideally suited for the harmful cytotoxins used in cancer therapy. In most cases, conjugation of the linker/cytotoxin unit to the antibody is accomplished through Michael reaction of cysteine side chains with maleimides. However, its reversibility limits the ADC’s circulation half-life and reduces the therapeutic window because of the systemic toxicity caused by released cytotoxins. In the course of this project, new linkers will be developed that enable the construction of stable S–C(sp2) conjugates through photoredox or nickel/photoredox dual catalysis. The reaction will be investigated using glutathione as cysteine-containing model substrate in combination with benzylamine and a short oligopeptide as cytotoxin-placeholders. The optimized conditions will then be applied to the functionalization of Trastuzumab, a commercially available antibody for targeting breast cancer cells. After fine-tuning the reaction conditions with an oligopeptide as cytotoxin-placeholder, a full ADC consisting of Trastuzumab and monomethyl auristatin E as cytotoxin will be assembled.