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.

四酸是5元的酮分酰胺，活性亚甲基化合物和弱酸（PKA 6.4）。 3-（多烯酰）四酸是活性的甲酸化合物和较强的酸（PKA 3.4）。后一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元酮分酰胺天然产物（五个靶标）和模型化合物（两个靶标），每个产品都有一个3-溶烯酰基。这些化合物应为芳香或非芳香族，并显示N-H或N-OH基序。它们可以被归为3-（元烯酰基）羟基吡啶酮。3-（polyenoyl）四酸是抗生素，抗病毒药，细胞毒素和/或杀真菌的。这使它们与药房和作物保护相关。 3-（聚烯酰）羟型吡啶酮会影响神经系统的信号转导。因此，它们代表了破坏神经细胞的疾病的化疗（阿尔茨海默氏症，帕金森氏症，脊髓损伤）。我们的主要目的是（继续）有效的合成方法的发展。首先，含有溴化的β-酮硫硫代植物应为中央三功能构建块，这是3（polyenoyl）的四酸和羟基吡啶酮的中央构件。在这方面，通过首次使用这种构建块在我们结构培养的3-（polyenoyl）四酸A-和ß-脂肪霉素的总合成中，我们感到鼓舞。其次，两个靶分子基的杂环应由迪克曼凝结产生。从ß-酮酰化的A-氨基酸酯中达到5元的酰基酮乳酸菌是众所周知的。相比之下，从ß-酮酰化β-氨基或ß-（羟基氨基）酸酯酸酯酸酯酸酯的研究较少得多，从而达到6元的酰基酮分型。此外，某些β-（羟基氨基）酸酯应由异恶唑烷酮制备。包含基序C（= o）-O-N，后者无环状膜酰胺。实际上，他们的化学融化一无所知。不过，它可能会很好地实现我们的目标。另一个主要目标是建立或完成七个目标分子的3D结构，其构型尚不清楚。为了阐明它们，我们打算以这样的数字合成每个这样化合物的对映体纯映体，以至于一个非对映异构体的特定旋转的绝对值必须等于已发表的值。然后，比较旋转的迹象将产生配置。MileitaronesA-C和D-E建议通过在Lemieux-Johnson条件下降解HTEIR Trienoyl侧链来阐明其甲基化的立体中心的构型。这应该用面向同步的甲基甲基含量。它们的立体结构应与对对映射的参考样品对（反过来源自合成）进行GC比较。我们在培养链霉菌，分离脂肪霉素，氧化降解并在（trifluoroacetyl）之后添加氧化的氧化剂时获得了潜在技术的专业知识。