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

天然和非天然苯并托酚酮和普维酮的高效合成。

• 批准号: 277682607
• 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: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/277682607?language=en
• 关键词: Efficient; Syntheses; Natural; Unnatural; Benzotropolones

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

1945 年，羟基环庚三烯酮被鉴定为真菌染料的核心。该核心被命名为托酚酮。它代表了第一个无电荷的同环非苯环芳香族化合物。苯到托酚酮的环化定义了3,4-和4,5-苯并托酚酮的结构。合成具有多种和任意可变取代模式的3,4-苯并托酚酮是我们项目的主要目标。合成 3,4-苯并托酚酮是防腐剂和紫外线吸收剂，可对抗微生物、逆转录病毒和肥胖。合成 3,4-苯并托波尔酮也是治疗痤疮和败血症的主要药物。茶黄素是另一种3.4-苯并托酚酮，对健康有益。它起源于茶的发酵。真正意义上的 3,4-苯甲托酚天然产物存在近 40 种变体。它们包含一种名为金曲霉酮的真菌染料。实现该化合物的首次全合成是我们项目的另一个目标。当我们试图通过氧化儿茶酚/连苯三酚混合物来获得橙曲酮时，它仍然难以捉摸 - 即。即，一步完成并且据称是仿生的。这种失败的一个可能原因是金曲胆酮类似于双(普维酮)，因为它含有两个α-芳基-γ-(芳基亚甲基)特窗酸部分。后者易于氧化，甚至自氧化，特别是当它们的芳基是多酚时。这是从密切相关的粉剂酸中众所周知的。因此，开发耐苯并托酚酮的普维酮合成方法是本项目的另一个愿望。我们的前期研究为三种此类普维酮路线奠定了基础。取代的 3,4-苯并托酚酮无法通过仿生方法获得，必须通过不同的方法来获得。此类替代方案的最新补充是在该项目的准备过程中出现的。它采用以下概念：3,4-苯并托波尔酮是苯并环庚二二酮的烯醇。苯并环庚二二酮源自水解苯并环庚二二酮单缩酮。后者源自邻-(2-烯丙基-2,2-二甲氧基乙酰基)苯乙烯的闭环复分解。进一步我们合成了第二代3,4-苯并托酚酮。为此，我们在复分解步骤后引入溴，并对所得溴代烯烃部分进行 C,C 偶联。具体来说，新型3,4-苯并托酚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-苯并托酚酮的结构空间；2）实现3,4-苯并托酚酮的首次全合成。 -苯并托酚酮-/bispulvinone 真菌染料 aurantricholonee 3) 开发第三代闭环复分解路线3,4-苯并托酚酮，无需酸性水解即可发挥作用 4) 建立获取普维酮的新途径 5) 测量所有新 3,4-苯并托酚酮的组蛋白脱甲基酶抑制作用。我们的初步研究揭示了相关的潜力

项目成果

Two-Step Synthesis of (Z)-3-Aryl-5-(arylmethylidene)butenolides by an Ivanov Reaction/Silver(I)-Catalyzed Lactonization/In Situ Dehydration Sequence

通过 Ivanov 反应/银 (I) 催化内酯化/原位脱水序列两步合成 (Z)-3-芳基-5-(芳基亚甲基)丁烯内酯

• DOI: 10.1055/s-0036-1588338
• 发表时间: 2017
• 期刊: Synthesis
• 作者: D. Hermann;D. Arican;R. Brückner
• 通讯作者: R. Brückner

Regioselective Bromination of Benzocycloheptadienones for the Synthesis of Substituted 3,4-Benzotropolones Including Goupiolone A.

苯并环庚二烯酮的区域选择性溴化用于合成取代的 3,4-苯并托酚酮（包括 Goupiolone A）

• DOI: 10.1002/chem.201700622
• 发表时间: 2017
• 期刊: Chemistry
• 作者: D. Arican;S. Braukmüller;R. Brückner
• 通讯作者: R. Brückner

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

• DOI: 10.1002/ejoc.202000256
• 发表时间: 2020-03
• 期刊: European Journal of Organic Chemistry
• 影响因子: 2.8
• 作者: Michael Kreibich;M. Gemander;D. Peter;Dharmendra B. Yadav;C. D. de Koning;M. Fernandes;I. Green