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

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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.