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

1945年，一个羟基环庚三烯酮被确定为真菌染料的核心。这个核被命名为tropolone。它是第一个无电荷的非苯类同环芳香族化合物。苯与邻苯酚酮的环化确定了3,4-和4,5-苯并邻苯酚酮的结构。合成3,4-苯并tropolone具有多种和任意可变的取代模式是我们项目的主要目标。合成3,4-苯并tropolone是防腐剂和紫外线吸收剂，对微生物，逆转录病毒和肥胖起作用。合成3,4-苯并tropolone也用于治疗痤疮和败血症。茶黄素是另一种对健康有益的3.4-苯并tropolone。它起源于茶的发酵。3,4-苯并tropolone天然产物在正确意义上的术语存在近40种变化。它们含有一种真菌染料，名为金霉酮。实现这种化合物的首次全合成是我们项目的另一个目标。当我们试图通过氧化儿茶酚/邻苯三酚混合物来获得它时，也就是说，在一个单一的步骤中，据说是仿生学的。这种失败的一个可能的原因可能是，金螺酮类似于双（普维酮），因为它含有两个-芳基- -（芳基甲基）四醛酸基团。后者易于氧化，甚至自氧化，特别是当它们的芳基是多酚时。这是众所周知的密切相关的普维尼酸。因此，开发耐苯并曲罗酮的普维酮合成是本项目的另一个愿望。在我们的预备研究中为三条这样的普尔维诺酮路线奠定了基础。取代的3,4-苯并咪唑酮类药物在仿生学上是不可接近的，必须通过不同的途径才能获得。这些选择的最新补充出现在这个项目的准备过程中。它采用以下概念：3,4-苯并tropolone是苯并环庚二酮的烯醇类。苯并环庚二烯酮是由苯并环庚二烯酮单酮水解而成。后者源于邻基苯乙烯（2-烯丙基-2,2-二甲氧基乙酰基）的合环复合体。进一步合成了第二代3,4-苯并唑波酮。为此，我们在反应步骤后引入溴，并用C、C偶联得到溴烯烃基团。具体来说，新的3,4-苯并唑波酮和普维酮的合成化学将从五个方面进行研究：1)探索第一代和第二代3,4-苯并tropolone的结构空间2)首次实现3,4-苯并tropolone /双pulvinone真菌染料aurantricholonee的全合成3)建立第三代3,4-苯并tropolone的闭环复分解途径，不需要酸性水解4)建立新的获得pulvinones的途径5)测量所有新3,4-苯并tropolone的组蛋白去甲基化酶抑制作用。我们的初步研究揭示了一种相关的潜力

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