Total synthesis and semi synthetic derivatization of [13]cytochalasans

细胞松弛素是一类具有广泛生物学功能的真菌聚酮-氨基酸杂合代谢产物。细胞松弛素的标志是它们的三环核心结构，其中大小可变的大环与衍生自氨基酸的双环异吲哚酮系统融合。细胞松弛素天然产物家族的11个已知亚类在稠合大环的大小及其氧化模式以及异吲哚酮核心的6元环中的氧化模式方面不同。在一些受尊敬的亚类的代表中，通过将大环融合到多环框架中来实现额外的结构多样性，甚至已知非大环细胞松弛素。尽管所有可用的生物学数据细胞松弛素，一个全面的图片的结构-活性关系（SAR）的具体活动或结构的动机（环大小，氧化模式，取代基）的尊重细胞松弛素亚类和不同的生物靶点解决它们之间的相关性仍然是失踪。尽管已经发表了几种已知细胞松弛素亚类的特定代表的全合成，但它们中没有一种是针对细胞松弛素亚类的[13]。由于天然细胞松弛素的获取有限，仅进行了很少的半合成衍生化研究，仅限于[11]细胞松弛素。因此，还没有关于[13]细胞松弛素的综合性合成研究能够阐明掺入的氨基酸、氧化模式或大环大小对生物活性和靶点选择性的SAR。此外，考虑到已经阐明的导致细胞松弛素的生物合成途径，我们可以预期自然界中存在形式上缺失的细胞松弛素亚类，这些亚类可以从生物合成的角度形成，但还没有从天然来源中分离出来。因此，从细胞松弛素天然产物家族中可能会发现更多隐藏的生物活性。在本项目中，一方面，我们计划将通过发酵获得的天然[13]细胞松弛素衍生化，另一方面，通过后期衍生化策略，聚合和可变的合成途径进入[13]细胞松弛素的亚类，并产生几种[13]细胞松弛素衍生物。此外，我们的目标是基于开发的合成，合成访问正式失踪的23-氧杂-[13]细胞松弛素亚类。因此，我们将提供适当的[13]细胞松弛素衍生物用于生物学评价，目标识别和成像目的，并使DFG研究人员小组CytoLabs内的不同合作伙伴能够对特定生物活性进行系统全面的SAR研究。

Cytochalasans comprise a diverse group of fungal polyketide-amino acid hybrid metabolites with a wide range of biological functions. A hallmark of the cytochalasans is their tricyclic core structure in which a size-variable macrocycle is fused to a bicyclic isoindolone system derived from an amino acid. The eleven known subclasses of the cytochalasan natural product family differ in the size of the fused macrocycle and its oxidation pattern as well as the oxidation pattern in the 6-membered ring of the isoindolone core. In some representatives of the respected subclasses additional structural diversity is achieved by fusion of the macrocycle into polycyclic frameworks and even non-macrocyclic Cytochalasans are known. Despite all available biological data on cytochalasans, a comprehensive picture of the structure-activity relationships (SAR) for specific activities or of the correlation between the structural motives (ring sizes, oxidation pattern, substituents) of the respected cytochalasan subclasses and the different biological targets addressed by them is still missing. Although, several total syntheses for specific representatives of known cytochalasan subclasses have been published, none of them has been targeting the subclass of [13]cytochalasans. As access to natural cytochalasans is limited, only very few semi-synthetic derivatization studies have been made, only limited to [11]cytochalasans. Thus, there are no comprehensive synthetic studies on [13]cytochalasans enabling the elucidation of SAR of incorporated amino acid, oxidation pattern or macrocycle size on the biological activities and target selectivity.Furthermore, considering the biosynthetic pathways leading to cytochalasans already elucidated, we can expect that there are formally missing cytochalasan subclasses existing in nature, which could be formed from a biosynthetically perspective, but have not been isolated from natural sources yet. Thus, there might be even more hidden biological activity to discover from the cytochalasan natural product family.Within the present project, on the one hand, we plan to derivatize natural [13]cytochalasans obtained by fermentation and on the other hand develop an efficient, convergent and variable synthetic access to the subclass of [13]cytochalasans via a late-stage derivatization strategy and generate several [13]cytochalasan derivatives. Furthermore, we aim to synthetically access the formally missing subclass of 23-oxa-[13]cytochalasans based on the developed synthesis. Thus, we will provide appropriate [13]cytochalasan derivatives for biological evaluation, target identification and imaging purposes and enable systematic comprehensive SAR studies for specific biological activities by different collaboration partners within the envisaged DFG Researcher Group CytoLabs.