Total synthesis and semi synthetic derivatization of [13]cytochalasans

细胞chalasans由多种真菌聚酮-氨基酸杂交代谢物组成，具有广泛的生物学功能。细胞chalasans的一个标志是它们的三环核心结构，其中一个大小可变的大环融合到一个由氨基酸衍生的双环异吲哚酮系统。已知的11个细胞查拉桑天然产物亚类在融合大环的大小和氧化模式以及异吲哚酮核心6元环的氧化模式上存在差异。在一些受尊敬的亚类的代表中，额外的结构多样性是通过将大环融合到多环框架中来实现的，甚至是非大环的Cytochalasans也是已知的。尽管有关于细胞chalasans的所有可用的生物学数据，但对于特定活性的结构-活性关系（SAR）或受尊敬的细胞chalasan亚类的结构动机（环大小，氧化模式，取代基）与它们所处理的不同生物学靶标之间的相关性的全面图景仍然缺乏。虽然已经发表了几种已知细胞chalasan亚类特定代表的全合成，但没有一种是针对[13]细胞chalasan亚类的。由于天然细胞链的获取途径有限，仅进行了很少的半合成衍生化研究，仅局限于[11]细胞链。因此，目前还没有全面的合成研究能够阐明掺入氨基酸、氧化模式或大环大小对生物活性和靶标选择性的SAR。此外，考虑到已经阐明的导致细胞chalasan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chalasan亚类，这些亚类可以从生物合成的角度形成，但尚未从自然来源中分离出来。因此，可能有更多隐藏的生物活性从细胞查拉桑天然产物家族中发现。在本项目中，我们一方面计划对发酵获得的天然[13]细胞chalasans进行衍生化，另一方面，通过后期衍生化策略，开发一种高效、收敛和可变的合成途径，获得[13]细胞chalasans亚类，并生成几种[13]细胞chalasan衍生物。此外，我们的目标是在已开发的合成的基础上，合成形式上缺失的23-oxa-[13]细胞chalasans亚类。因此，我们将提供适当的[13]细胞查拉珊衍生物，用于生物学评估、目标识别和成像目的，并在设想的DFG研究小组细胞实验室中，由不同的合作伙伴对特定的生物活动进行系统的综合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.