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.

Tetramic 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)tetramic 酸是活性次甲基化合物和更强的酸 (pKa 3.4)。此外，我们计划合成类似的六元酮内酰胺天然产物（五个目标）和模型化合物（两个目标），每个都有一个这些化合物应为芳香族或非芳香族，并显示 N-H 或 N-OH 基序。它们可分为 3-(多烯酰基)羟基吡啶酮。3-(多烯酰基)特特拉姆酸是抗生素、抗病毒剂、细胞毒剂和药物。 /或杀菌剂。这使得它们与药学和作物保护相关。因此，它们影响神经系统中的信号转导。用于破坏神经细胞的疾病（阿尔茨海默病、帕金森病、脊髓损伤）的化学疗法。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-酮硫酯应成为核心。 3-(多烯酰基)四酸和羟基吡啶酮的三功能结构单元在这方面我们对首次使用这样的结构感到鼓舞。其次，两个目标分子基团的杂环应由 Dieckmann 缩合产生，从而从 β-酮酰化 a 得到 5 元酰基酮内酰胺。相反，β-氨基酸酯是众所周知的，由此得到6-元酰基酮内酰胺。 β-酮酰化β-氨基-或β-(羟基氨基酸)酸酯的研究要少得多。此外，某些β-(羟基氨基酸)酸酯应由含有基序C(= O)-O-N的异恶唑烷酮制备。没有环状 Weinreb 酰胺，但实际上对其烯醇化学性质一无所知。但它可能很好地满足我们的目标。另一个主要目标。正在建立或完成七个目标分子的 3D 结构，其构型尚未（完全）已知。为了阐明它们，我们打算合成每个此类化合物的对映体纯非对映异构体，其数量为一个化合物的比旋光度的绝对值。非对映异构体必须等于公布的值，然后比较旋转符号才能得出构型。militarinones A-C 和 D-E 建议通过以下方式澄清其甲基化立体中心的构型。在 Lemieux-Johnson 条件下降解其三烯酰基侧链，这应该会产生具有顺式甲基对的醇，其立体结构应与对映体参考样品对进行 GC 比较（这又应源于合成）。我们在培养链霉菌、分离α-脂霉素、氧化降解以及对所得醇进行气相色谱分析时获得了基础技术方面的专业知识。 (三氟乙酰基)化后。