Diversity-Oriented Synthesis of Macrocyclic Scaffolds Utilizing Organo- and Metal Catalysis

• Applicant: Dr. André Grossmann
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245388588

The ability of small molecules to interact with macromolecules and modulate their function has emerged as a powerful tool for work on signaling pathways in biological systems - an important domain in modern medical sciences. In this context, a systematic approach towards structurally diverse small molecule libraries is called Diversity Oriented Synthesis (DOS).In the outlined research project I will introduce an efficient DOS approach towards a library of macrocyclic polyesters and polyamides, based on the pluripotency of alpha, beta-unsaturated aldehydes and dienes, and the possibility of using enals and unactivated alkenes or alkynes orthogonally. In line with the recommendations of the Schreiber's build/couple/pair algorithm, my project consists of three stages. First, I will build an appropriate number of pre-functionalized building blocks. Subsequently, these building blocks will be coupled utilizing N heterocyclic carbene catalyzed reactions. Finally, in the pairing phase the building block chain will be cyclized via ruthenium catalyzed enyne-ring-closing metathesis (RCM). In order to increase the overall diversity of the final library, the resulted diene functionality will be used as a starting point for additional post-RCM modifications. As a result, the synthesized collection of macrocycles will broadly occupy the chemical/biological space containing all four principle components of diversity: appendage diversity, functional group diversity, stereochemical diversity and skeletal (scaffold) diversity. I plan to conclude this project with phenotypic bioactivity tests of the macrocyclic library members. In this context, my focus will lie on the antibacterial activity against different pathogenic, multidrug-resistant bacterial strains. Furthermore, I will explore the ability of the synthesized macrocyclic compounds to modify protein-protein interactions and multi-protein complexes relevant in the process of cancer cell proliferation.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. David R. Spring