Determination of Absolute Configurations of Depsipeptides Rakicidin C and Rakicidin F through a systematic synthesis strategy

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Development of new antibiotics and cytostatics represents a major challenge due to increasing resistances. Therefore, it is essential to identify potent compounds with new modes of action. Here, the scaffolds of natural products are often used as an inspiration. In the case of chiral drugs, different enantiomers can exhibit different pharmacological properties. Hence, the total synthesis and determination of absolute configurations is an important task in the development of new active substances.The Rakicidin family of natural products represents a particularly attractive synthetic target, as their members can either be cytotoxic or antibacterial. In this project, we aim to determine the absolute configuration of two new natural products, Rakicidin C and Rakicidin F. This could be the basis for the development of new active substances from this subclass of Rakicidins with stereogenic centers in the lipid side chain.The main strategy is to determine the absolute configuration of the stereo cascades step-by-step by employing encoded diastereomeric mixtures, which will be obtained using lithiation-borylation sequences.The activity of the Rakicidin family is highly dependent on the structure of the lipid side chain. Thus, after successful determination of the absolute configurations of Rakicidin C and F, two new Rakicidin derivatives with all-syn- and all-anti- stereo cascades will be synthesised. These derivatives could be utilised for the study of structure-activity-relationships. Furthermore, their NMR data could act as a platform for determining the absolute configuration of currently undiscovered members of the Rakicidin family.