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

由于耐药性的增加，新抗生素和细胞抑制剂的开发是一个重大挑战。因此，必须确定具有新作用模式的有效化合物。在这里，天然产品的支架通常被用作灵感。在手性药物的情况下，不同的对映异构体可以表现出不同的药理学性质。因此，全合成和确定绝对构型是开发新活性物质的重要任务。Rakicidin家族的天然产物代表了特别有吸引力的合成目标，因为它们的成员可以是细胞毒性的或抗菌的。本项目的目标是确定两个新天然产物Rakicidin C和Rakicidin F的绝对构型。这可能是从这个在脂质侧链中具有立体中心的Rakicidin亚类开发新活性物质的基础。主要策略是通过使用编码的非对映体混合物逐步确定立体级联的绝对构型，该混合物将使用锂化-硼化序列获得。Rakicidin家族的活性高度依赖于脂质侧链的结构。因此，在成功确定Rakicidin C和F的绝对构型之后，将合成具有全顺式和全反式立体级联的两种新的Rakicidin衍生物。这些衍生物可用于构效关系的研究。此外，他们的NMR数据可以作为确定Rakicidin家族目前未发现成员的绝对构型的平台。

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.