Total Synthesis - Partly Including the 3D-Assignments of Hitherto Unknown Stereocenters - of 3-(Polyenoyl)tetramic Acid and 3 (Polyenoyl)hydroxypyridone Natural Products: Militarinones, Farinosone B, Fumosorinone, and two Anomeric Aurantosides

3-(多烯酰基)四酸和3(多烯酰基)羟基吡啶酮天然产物的全合成 - 部分包括迄今为止未知的立体中心的3D分配

• 批准号: 392556093
• 负责人: Professor Dr. Reinhard Brückner
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392556093?language=en
• 关键词: Total; Synthesis; Partly; Including; 3D

Tetramic acids are 5-membered ketolactams, active methylene-compounds, and weak acids (pKa 6.4). 3-(Polyenoyl)tetramic acids are active methine-compounds and stronger acids (pKa 3.4). Four natural compounds of the latter type belong to our synthetic goals. Moreover, we plan to synthesize analogous 6-membered ketolactam natural products (five targets) and model compounds (two targets), each with a 3-polyenoyl group. These compounds shall be aromatic or non-aromatic and display an N-H or N-OH motif. They can be binned as 3-(polyenoyl)hydroxypyridones.3-(Polyenoyl) tetramic acids are antibiotics, antivirals, cytotoxics and/or fungicides. This makes them relevant for pharmacy and crop protection. 3-(Polyenoyl)hydroxypyridones affect signal transduction in the nervous system. Therefore, they represent leads for the chemotherapy of diseases destroying nerve cells (Alzheimer's, Parkinson's, injuries of th spinal cord).A main objective of ours is (continuing) the development of efficient synthetic methodology. Firstly, bromoolefin-containing ß-ketothioesters shall be the central trifunctional building block both of 3-(polyenoyl)tetramic acids and hydroxypyridones. We feel encouraged in this regard by the first-time use of such a building block in our structure-elucidating total synthesis of the 3-(polyenoyl)tetramic acids a- and ß-lipomycin. Secondly, the heterocycle of both target molecule groups shall result from Dieckmann condensations. Reaching 5-membered acylketolactames thereby from ß-ketoacylated a-amino acid esters is well-known. In contrast, reaching 6-membered acylketolactames thereby from ß-ketoacylated ß-amino- or ß-(hydroxyamino)acid esters is much less studied. Moreover, certain ß-(hydroxyamino)acid esters shall be prepared from isoxazolidinones. Containing the motif C(= O)-O-N, the latter are no cyclic Weinreb amides. Virtually nothing is known about their enolate chemistry. Just it might serve our objectives well, though.Another main objective is establishing or completing the 3D structure of the seven target molecules, whose configurations are not (fully) known. For elucidating them, we intend to synthesize enantiomerically pure diastereomers of each such compound in such numbers that the absolute value of the specific rotation of one diastereomer must equal the published value. Comparing signs of rotation will then yield the configuration.The militarinones A-C and D-E suggest to have the configuration of their methylated stereocenters clarified by degrading hteir trienoyl side-chain under Lemieux-Johnson conditions. This should deliver alcohols with a syn-oriented pair of methyl groups. Their stereostructure should yield to GC comparisons with pairs of enantiomorphic reference samples (which, in turn, shall stem from synthetis). We acquired expertise in the underlying techniques when cultivating Streptomyces, isolating a-lipomycin, degrading it oxidatively, and GC-ing the resulting alcohols after (trifluoroacetyl)ation.

特特拉姆酸是5元酮内酰胺、活性亚甲基化合物和弱酸（pKa 6.4）。3-（多烯酰基）特特拉姆酸是活性次甲基化合物和更强的酸（pKa 3.4）。后一种类型的四种天然化合物属于我们的合成目标。此外，我们计划合成类似的6-元酮内酰胺天然产物（5个目标）和模型化合物（2个目标），每个都有一个3-多烯酰基。这些化合物应该是芳香族或非芳香族的，并且显示N-H或N-OH基序。它们可以被归类为3-（多烯酰基）羟基吡啶酮。3-（多烯酰基）特特拉姆酸是抗生素、抗病毒药、细胞毒素和/或杀真菌剂。这使得它们与制药和作物保护相关。3-（多烯酰基）羟基吡啶酮影响神经系统中的信号转导。因此，它们代表了破坏神经细胞的疾病（阿尔茨海默氏症、帕金森氏症、脊髓损伤）的化学疗法的先导。我们的主要目标是（继续）开发有效的合成方法。首先，含溴烯烃的β-酮硫酯应该是3-（多烯酰基）特特拉姆酸和羟基吡啶酮的中心三官能结构单元。在这方面，我们感到鼓舞的第一次使用这样的积木在我们的结构阐明3-（多烯酰基）特特拉姆酸α-和β-脂霉素的全合成。其次，两个目标分子基团的杂环应来自Dieckmann缩合。由此从α-酮酰化α-氨基酸酯得到5-元酰基酮内酰胺是众所周知的。相比之下，从β-酮酰化的β-氨基-或β-（羟基氨基）酸酯得到6-元酰基酮内酰胺的研究要少得多。此外，某些β-（羟基氨基）酸酯应当由异恶唑烷酮制备。含有C（= O）-O-N基序的非环状Weinreb酰胺。事实上，人们对它们的烯醇化物化学性质一无所知。然而，这可能很好地服务于我们的目标，另一个主要目标是建立或完成七个目标分子的3D结构，其构型还不（完全）已知。为了阐明它们，我们打算合成每种化合物的对映体纯的非对映体，其数量使得一种非对映体的比旋光度的绝对值必须等于公布的值。通过比较旋转符号，可以得到构型。militarinone A-C和D-E表明，通过在Lemieux-Johnson条件下降解其三烯酰基侧链，可以澄清其甲基化立体中心的构型。这应该提供具有顺式取向的甲基对的醇。它们的立体结构应产生GC与成对的对映体参比样品（反过来，应来自合成）的比较。我们在培养链霉菌、分离α-脂霉素、氧化降解和（三氟乙酰基）化后对所得醇进行GC分析时获得了基础技术方面的专业知识。