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。这个核心被命名为tropolone。它代表了第一个不带电荷的单环非苯型芳香族化合物。苯成环环酚酮定义了3，4-和4，5-苯并环酚酮的结构。本课题的主要目标是合成具有不同取代模式的3，4-苯并环庚三烯酚酮类化合物。合成3，4-苯并环庚三烯酚酮是防腐剂和紫外线吸收剂，并对微生物，逆转录病毒和肥胖症起作用。合成的3，4-苯并环庚三烯酚酮也是治疗痤疮和脓毒症的主要药物。茶黄素是另一种3.4-苯并托酚酮，对健康有益。它起源于发酵给茶。3，4-苯并环庚三烯酚酮天然产物在该术语的正确意义上存在近40种变化。它们含有一种真菌染料，名为橙毛酚酮。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/连苯三酚混合物的氧化来获得橙皮酚酮时，仍然很难得到。例如，在一个单一的步骤和所谓的仿生学。这种失败的一个可能的原因可能是橙草酮类似于双（蒲维酮），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。这是众所周知的，从密切相关的垫状酸。因此，开发苯并托酚酮耐受性的pulvinone合成是本项目的另一个迫切需要。三个这样的pulvinone路线的基础在我们的预备研究中建立。取代的3，4-苯并环庚三烯酚酮是不可接近的生物模拟物，必须通过不同的方法获得。这类替代办法的最新补充是在筹备这一项目时出现的。它采用以下概念：3，4-苯并环庚二烯二酮的烯醇。苯并环庚二烯二酮来源于水解苯并环庚二烯二酮单缩酮。后者来源于邻-（2-烯丙基-2，2-二甲氧基乙酰基）苯乙烯的闭环复分解反应。进一步进行，我们合成了第二代3，4-苯并环庚三烯酚酮。为此，我们在复分解步骤后引入溴，并将所得溴烯烃部分C，C-偶联。详细地说，新的3，4-苯并环庚三烯酚酮和蒲维酮的合成化学应在五个方面进行研究：1）探索第一代和第二代3，4-苯并环庚三烯酚酮的结构空间2）首次实现了3，4-苯并环庚三烯酚酮-/双蒲维酮真菌染料橙三胆酮的全合成3）开发了第三代3，4-苯并环庚三烯酚酮的闭环复分解路线，其不需要酸性水解就能起作用4）建立新的获得垫维酮的途径5）测量所有新的3，4-苯并环庚三烯酚酮的组蛋白脱甲基酶抑制作用。我们的初步研究显示

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

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

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