Peptide-Based Catalysts for the Enantio-, Diastereo-, and Site-Selective Functionalization of Complex Organic Molecules with Reactive Nitrogen Containing Heterocycles

批准的药物中有很大一部分是复杂分子，天然产物的全合成和半合成衍生化都为创新的新药候选提供了途径。然而，高复杂性化合物的选择性修饰是一个巨大的挑战，需要新的合成转化策略。在这一点上，对映体、非对映体和位置选择性在官能化中起着关键作用，因为同时存在多个通常相似的官能团会导致具有潜在不同生物活性的异构体。在这种情况下，基于多肽的催化剂是强有力的工具，因为它们的选择性是基于与底物的多个官能团的相互作用。通过催化剂和底物的缔合，催化活性中心被定位在底物上特定的反应中心附近，从而诱导了立体选择性和位置选择性。斯科特·J·米勒教授的团队率先开发了小β转角多肽，其中四个氨基酸残基形成二级结构，在对映选择性催化中具有非常有利的性质。在这项研究项目中，将开发基于多肽的催化剂，用于日益复杂的分子中烯烃的对映体、非对映体和位置选择性氮杂环化以及亚硝基Diels-Alder反应。这将通过根据催化活性侧链的变化(例如Brnsted酸、过渡金属或Lewis碱的配体)以及底物和试剂结合的相互作用位置的变化来系统地筛选β转肽来实现。烯烃底物稍后将包括具有内在抗肿瘤或抗生素活性的天然产物，如雷帕霉素、寡霉素A和硫链菌素。它们都是通过生物合成获得足够数量的。此外，对其与生物靶标的相互作用机理进行了深入的研究，使得根据构效关系进行衍生化设计成为可能。对所获得的衍生物的生物活性的研究将完成这一研究项目，在这方面必须指出两个潜在的优势：氮杂环丙烷基团能够与亲核试剂(如DNA)开环，这也是抗生素和抗癌丝裂霉素类生物碱以及阿奇霉素的关键特征。此外，引入的活性氮杂环具有多种后续官能化的可能性，其目的可能是改变极性、标记的附着以及增强或阻断结合部位。本研究项目中开发的所有方法都不限于应用于半合成，而是代表了复杂分子选择性官能化的通用工具箱。

A large proportion of approved pharmaceuticals are complex molecules, and both total synthesis and semisynthetic derivatization of natural products grant access to innovative new drug candidates. However, the selective modification of compounds with high complexity is a significant challenge and requires new synthetic transformation strategies. In this regard, enantio-, diastereo-, and site-selectivity play a key role in functionalization, since the simultaneous presence of multiple, and often similar, functional groups results in isomers with potentially different biological activity. Peptide-based catalysts serve as powerful tools in this context, as their selectivity is based on interactions with multiple functional groups of the substrates. Through the association of catalyst and substrate, the catalytically active sites are positioned in proximity to specific reactive sites on the substrates, and thus stereo- and site-selectivity is induced. The group of Prof. Scott J. Miller has pioneered the development of small beta-turn peptides, in which four amino acid residues nucleate secondary structures with highly beneficial properties in enantioselective catalysis. In this research project, peptide-based catalysts for the enantio-, diastereo-, and site-selective aziridination, as well as the nitroso Diels-Alder reaction, of alkene groups within increasingly complex molecules will be developed. This will be realized through systematic screening of beta-turn peptides based on variation of catalytically active side chains - e.g. Brønsted acids, ligands for transition metals or Lewis bases - as well as interaction sites for binding of substrates and reagents. The alkene substrates will later include natural products with intrinsic antitumor or antibiotic activity, such as rapamycin, oligomycin A, and thiostrepton. They are all available in sufficient quantities through biosynthesis. In addition, their mechanism of interaction with biological targets is well studied, which allows the design of derivatization according to structure-activity relationships.The investigation of biological activities of the obtained derivatives will complete the research project, and two potential advantages have to be pointed out in this regard: Aziridine groups are capable of ring opening with nucleophiles - such as DNA - which also represents the key feature of antibiotic and anticancer mitomycinoid alkaloids as well as azinomycin. Additionally, the introduced reactive nitrogen heterocycles allow a multitude of subsequent functionalization possibilities, which may aim for changing polarity, attachment of labels and enhancing or blocking of binding sites.All methods developed in this research project are not limited to application in semisynthesis, but rather represent general toolboxes for the selective functionalization of complex molecules.