Efficient Syntheses of Natural and Unnatural Benzotropolones and Pulvinones. Total Synthesis of the Fungal Dye Aurantricholone

1945年，一种羟基环庚三烯酮被确定为真菌染料的核心。这个核心被命名为特罗波龙。它代表了第一个无电荷的等环非苯类芳香族化合物。苯的环化反应定义了3，4-和4，5-苯并三苯丙酮的结构。本项目的主要目标是合成具有不同取代模式和任意可变取代模式的3，4-苯并三酮。人工合成的3，4-苯丙酮是防腐剂和紫外线吸收剂，可以对抗微生物、逆转录病毒和肥胖症。人工合成的3，4-苯丙酮也是治疗痤疮和败血症的先导。茶黄素是另一种3.4-苯并孕酮，对健康有益。它起源于给茶的发酵。真正意义上的3，4-苯并三苯丙酮天然产物存在于近40种变体中。它们含有一种名为金曲酮的真菌染料。实现该化合物的首次全合成是我们项目的另一个目标。当我们试图通过邻苯二酚/邻苯三酚混合物的氧化来获得金曲酮时，它仍然是难以捉摸的--也就是说，一步完成并被认为是仿生的。这一失败的一个可能原因可能是，极三酮类似于双(垫片酮)，因为它含有两个α-芳基-伽马-(芳亚甲基)四酸部分。后者容易氧化，甚至自氧化，特别是当它们的芳基是多酚时。这是从密切相关的垫状病毒中众所周知的。因此，开发耐苯并托波酮的垫普诺酮合成是本项目的另一个愿望。我们的前期研究为三条这样的垫普诺酮路线奠定了基础。取代的3，4-苯并三苯丙酮是生物仿生学上无法获得的，必须通过不同的方法来获得。这类替代品的最新成员是在该项目的筹备过程中出现的。它采用如下概念：3，4-苯并三苯丙酮是苯并环七二烯二酮的烯醇。苯环七二烯二酮类化合物是苯环七二烯二酮类化合物的水解物。后者来源于邻位-(2-烯丙基-2，2-二甲氧基乙酰基)苯乙烯的开环歧化反应。进一步合成了第二代3，4-苯并三苯丙酮。为此，我们在歧化步骤后引入溴和C，C-偶联生成的溴烯烃部分。1)探索第一代和第二代3，4-苯并三酮的结构空间；2)首次实现3，4-苯并三酮真菌染料Auantricholonee的首次全合成；3)开发第三代3，4-苯并三酮的闭环易位反应路线；4)建立新的通向3，4-苯并三酮的新途径；5)测定所有新的3，4-苯并三酮的组蛋白去甲基酶抑制作用。我们的初步研究揭示了一个相关的潜力

In 1945 a hydroxycycloheptatrienone was identified as the core of a fungal dye. This core was named tropolone. It represented the first charge-free isocyclic non-benzenoid aromatic compound. The annulation of benzene to tropolone defines the structures of 3,4- and 4,5-benzotropolone. The synthesis of 3,4-benzotropolones of diverse and arbitrarily variable substitution patterns is the main objective of our project. Synthetic 3,4-benzotropolone are preservatives and UV absorbers and act against microbes, retroviruses, and obesity. Synthetic 3,4-benzotropolone are also leads for the therapy of acne and sepsis. Theaflavin is another 3.4-benzotropolone, which is beneficial for health. It originates from the fermentation giving tea. 3,4-Benzotropolone natural products in the proper sense of the term exist in almost 40 variations. They comprise a fungal dye named aurantricholone. Achieving the first total synthesis of this compound is another goal of our project. Aurantricholone remained elusive when we tried to gain it by the oxidation of catechol/pyrogallol mixtures - i. e., in a single step and supposedly biomimetically. A likely reason for this failure could is that aurantricholone resembles a bis(pulvinone) because it contains two alpha-aryl-gamma-(arylmethylidene)tetronic acid moieties. The latter are prone to oxidations and even to autoxidation, particularly, when their aryl groups are polyphenols. This is well-known from the closely related pulvinic aicids. Hence, developing benzotropolone-tolerant pulvinone syntheses is another desideratum of this project.The foundations for three such pulvinone routes were established in our preparatory studies. Substituted 3,4-benzotropolones, which are inaccessible biomimetically, must be accessed by different approaches. The newest addition to such alternatives emerged from the preparation of this project. It employs the following concept: 3,4-Benzotropolone are enols of benzocycloheptadienediones. Benzocycloheptadienediones stem from hydrolyzing benzocycloheptadienedione monoketals. The latter originate from ring-closing metatheses of ortho-(2-allyl-2,2-dimethoxyacetyl)styrenes. Proceeding further we synthesized second generation 3,4-benzotropolones. To this end we introduced bromine after the metathesis step and C,C-coupled the resulting bromoolefin moieties. In detail, the synthetic chemistry of new 3,4-benzotropolones and pulvinones shall be studied in five regards: 1) Exploring the structural space of 1st and 2nd generation 3,4-benzotropolones 2) Realizing the first total synthesis of the 3,4-benzotropolone-/bispulvinone fungal dye aurantricholonee 3) Developing ring-closing metathesis routes to 3rd generation 3,4-benzotropolones, which work without an acidic hydrolysis 4) Establishing new access routes to pulvinones 5) Measuring the histone demethylase inhibitory effect of all new 3,4-benzotropolones. Our preliminary studies revealed a pertinent potential