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

四酸是五元酮内酰胺、活性亚甲基化合物和弱酸(pKa 6.4)。3-(多烯酰基)四酸是一种活性较强的亚甲基化合物(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，我们还计划合成类似的6元酮内酰胺类天然产物(5个目标)和模型化合物(2个目标)，每个化合物都带有3-聚烯酰基。这些化合物应该是芳香的或非芳香的，并显示N-H或N-OH基序。3-(多烯酰基)四酸是抗生素、抗病毒药物、细胞毒素和/或杀菌剂。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的信号转导。因此，它们代表着对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)进行化疗的先导。我们的一个主要目标是(继续)开发有效的合成方法学。首先，3-(聚烯酰基)四酸和羟基吡啶酮的中心三官能团均为含溴烯烃的芳基-酮硫酸酯。在这方面，我们感到鼓舞的是，首次在我们的结构中使用了这样的构建块-阐明了3-(多烯酰基)四酸a-和β-脂霉素的全合成。其次，两个目标分子基团的杂环都是由Dieckmann缩合形成的。因此，从β-酮酰化的α-氨基酸酯中得到5元的酰基酮内酯是众所周知的。相反地，从？酮酰化的？氨基或？(羟氨基)酸酯中得到6元的酰基酮内酯的研究要少得多。此外，还应从异恶唑烷酮制备某些β-(羟基氨基酸酯)酯。含有C(=O)-O-N基序，后者不是环状Weinreb酰胺。事实上，人们对它们的稀有化学一无所知。不过，这可能会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，这些分子的构型尚不(完全)已知。为了阐明它们，我们打算合成每个这样的化合物的对映体纯的非对映异构体，其数量使得一个非对映异构体的比旋光度的绝对值必须等于公布的值。比较旋转的迹象将得到构型。军事酮A-C和D-E建议在Lemieux-Johnson条件下通过降解hteir三烯酰基侧链来阐明其甲基化立体中心的构型。这应该提供带有一对以合成基为导向的甲基的醇。它们的立体结构应该与成对的对映体参考样品进行GC比较(这反过来又来自于合成)。我们在培养链霉菌，分离a-脂霉素，氧化降解它，以及(三氟乙酰化)后生成的醇的GC-GC方面获得了基本技术方面的专业知识。

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.