Building-Block Approach for Organic Synthesis

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The ability of chemists to create molecules with precise shape and functionality is central to development and growth for many research disciplines from medicine to materials. As known from industrial production modular processes are usually highly efficient and flexible, that is why Nature builds most molecules by connecting a very limited set of small molecules (so called building-blocks) in an assembly-line like process, hereby creating an unbelievable amount of diverse natural compounds. Therefore two building-blocks are activated and then brought together so that they form a new chemical bond. This is done by Nature with very high precision in a sequential way. For the most prominent cases (DNA/RNA/proteins) chemists already developed processes to copy the building-block approach from Nature with significant impact in science and technology. While the connection of amino acids (proteins) and nucleotides (DNA/RNA) is rather straightforward the controlled growth of carbon chains, which is central for making organic molecules, is much more challenging. Thus, synthesis of complex organic molecules remains a demanding task for specialists and for every single molecule a new route for the synthesis has to be designed from scratch. The aim of the proposed research project is to develop a strategy to adopt the building-block approach for the synthesis of highly complex organic molecules, the so called polyketides. Polyketides are a very large and diverse natural product family with many important biological activities leading to application in many pharmaceuticals and agrochemicals (antibiotics, antifungals, insecticides, etc.). That is why a building-block approach is desirable since it will allow the synthesis of these very important molecules much easier and faster (high efficiency). When using a standard set of building-blocks most polyketide structures can be prepared even by non-specialists. Importantly, this modular strategy will make it much easier to modify the molecules and study how the structure of the molecule affects the biological activity, finally leading to molecules with better properties (high flexibility). The first step is to design building-blocks and identify an eligible chemical transformation to selectively activate them in high precision. The set of building-blocks includes terminal units with one handle for connection and bifunctional ones with two handles. Next, the designed building-blocks will be synthesized in an efficient and reproducible way. This set of building-blocks will then be used for the synthesis of two antibiotics from the polyketide family in a highly efficient manner. This building-block strategy has great potential to open the field of organic synthesis to a much broader pool of scientist.