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

通过系统合成策略确定缩肽 Rakicidin C 和 Rakicidin F 的绝对构型

• 批准号: 412927050
• 负责人: Dr. Felix Pape
• 金额: --
• 依托单位: School of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/412927050?language=en
• 关键词: Determination; Absolute; Configurations; Depsipeptides; Rakicidin

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.

由于耐药性增加，开发新的抗生素和细胞抑制剂是一项重大挑战。因此，确定具有新作用方式的有效化合物是必要的。在这里，天然产品的支架经常被用作灵感。对于手性药物，不同的对映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一项重要任务。Rakicidin家族的天然产物代表了一个特别有吸引力的合成靶标，因为它们的成员可以是细胞毒性或抗菌的。本项目旨在确定Rakicidin C和Rakicidin f两种新天然产物的绝对构型，为从该亚类Rakicidin中开发具有脂侧链立体中心的新活性物质奠定基础。主要策略是通过使用锂化-硼化序列获得编码的非对映异构体混合物，逐步确定立体级联的绝对构型。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的绝对构型后，将合成两种具有全顺和全反立体级联的Rakicidin衍生物。这些衍生物可用于构效关系的研究。此外，他们的核磁共振数据可以作为确定目前未发现的Rakicidin家族成员的绝对构型的平台。