Novel Furan Cycloaddictions for Preparation of Medicinally Important Compounds

用于制备重要药用化合物的新型呋喃环化

• 批准号: 8102728
• 负责人: JAMES W HERNDON
• 金额: $ 21万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102728
• 关键词: Aldehydes; Alder plant; Alkaloids; Alkenes; Alkynes; Amides; Antineoplastic Agents; Apomorphine; Aporphines; Area; Biological Factors; Chemicals; Chromium; Complex; Coupling; Cyclization; Development; Diels Alder reaction; Dopamine Receptor; Electrons; Esters; Event; Furans; Goals; Hydrazones; Hypertension; Malignant Neoplasms; Marines; Methodology; Methods; Microtubule Polymerization; Microtubules; Parkinson Disease; Pattern; Phase; Population; Preparation; Procedures; Process; Protocols documentation; Pyrroles; Quality of life; Reaction; Relative (related person); Route; Scheme; Screening procedure; System; Testing; Variant; Work; analog; base; carbene; cycloaddition; design; diazene; eleutherobin; enantiomer; hypertension treatment; nervous system disorder; nitrene; novel; preference; stereochemistry; undecane

DESCRIPTION (provided by applicant): The work in this proposal involves the development of new furan and pyrrole-based cycloaddition reactions that result in the formation of complex ring systems from simple and readily available components. The cycloaddition mode depends upon the synthetic route and the substitution pattern for the furan/pyrrole core. The [8+2]-cycloaddition mode occurs when alkynes couple with dienylfurans. This reaction assembles the core ring system (furan-bridged ten-membered ring) of the marine-derived experimental anti-cancer agent eleutherobin. The full synthetic potential of this reaction will be developed, including delineation of the scope, limit, and stereochemistry of the [8+2]-cycloaddition followed by a study of the reactivity profile for densely functionalized [8+2]-cycloadducts. These chemical processes will be employed in the design of new anti-cancer agents that structurally resemble eleutherobin. The ability of these compounds to promote microtubule polymerization will be tested, and active candidates will be further tested as anti-cancer agents. The coupling of chromium carbene complexes with ortho-alkynylbenzoyl derivatives leads to activated furan/pyrrole rings, which undergo efficient cycloaddition with a variety of alkenes and alkynes. A variant of this process will be developed where highly unsaturated chromium carbene complexes afford phenanthroid ring systems in a formal [5+5]-cycloaddition reaction. These reactions are the cornerstone for versatile and efficient synthetic approaches to tanshinones, useful for the treatment of hypertension, and to apomorphine, a dopamine receptor useful for the treatment of Parkinson's disease. Work in this proposal provides structurally complex and medicinally important compounds from simple and readily available components. The reaction process can conveniently provide compounds (or more importantly structural analogs) that have shown potent anti-cancer activity, anti-hypertension activity, and activity against neurologic disorders such as Parkinson's disease. These are all very common ailments that negatively impact the quality of life a large portion of the U.S. population.

描述（由申请人提供）：本提案中的工作涉及开发新的呋喃和吡咯基环加成反应，这些反应导致从简单且易于获得的组分形成复杂的环体系。环加成模式取决于合成路线和呋喃/吡咯核的取代模式。当炔与二烯基呋喃偶联时，发生[8+2]-环加成模式。该反应组装了源自海洋的实验性抗癌剂五加苷的核心环系统（呋喃桥接的十元环）。将开发该反应的全部合成潜力，包括描绘[8+2]-环加成的范围、限制和立体化学，然后研究密集官能化[8+2]-环加成物的反应性概况。这些化学过程将用于设计结构上类似于五加苷的新抗癌剂。将测试这些化合物促进微管聚合的能力，并将进一步测试活性候选物作为抗癌剂。铬卡宾络合物与邻炔基苯甲酰基衍生物的偶联导致活化的呋喃/吡咯环，其与各种烯烃和炔进行有效的环加成。将开发该方法的变体，其中高度不饱和的铬卡宾络合物在正式的[5+5]-环加成反应中提供菲咯啉环系统。这些反应是丹参酮（用于治疗高血压）和阿扑吗啡（用于治疗帕金森病的多巴胺受体）的通用和有效合成方法的基石。 本提案中的工作从简单且容易获得的组分提供了结构复杂且具有医学重要性的化合物。该反应过程可以方便地提供已经显示出有效的抗癌活性、抗高血压活性和针对神经障碍如帕金森病的活性的化合物（或更重要的是结构类似物）。这些都是非常常见的疾病，对美国大部分人口的生活质量产生了负面影响。

项目成果

Synthesis of benzocycloheptanones through coupling of δ,ε-unsaturated chromium carbene complexes and 2-alkynylbenzoyl derivatives.

通过 δ,δ-不饱和铬卡宾配合物和 2-炔基苯甲酰衍生物的偶联合成苯并环庚酮。

• DOI: 10.1021/ol200825j
• 发表时间: 2011
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Patti,RajeshKumar;Waynant,KristopherV;Herndon,JamesW
• 通讯作者: Herndon,JamesW

Preparation of phenalenes and hydronaphthacenes through tandem alkyne Fischer-carbene complex coupling and inter- or intramolecular Diels-Alder reactions.

通过串联炔烃费歇尔-卡宾配合物偶联和分子间或分子内狄尔斯-阿尔德反应制备菲那烯和氢化并四苯。

• DOI: 10.1016/j.tetlet.2011.06.006
• 发表时间: 2011
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Patti,RajeshKumar;Duan,Shaofeng;Wang,Zhipeng;Herndon,JamesW
• 通讯作者: Herndon,JamesW

Electronic Control of Product Distribution in the [5+5]-Coupling of ortho-Alkynylbenzaldehyde Derivatives and γ,δ-Unsaturated Carbene Complexes.

[5 5]-邻炔基苯甲醛衍生物和γ,γ-不饱和卡宾配合物偶联中产物分布的电子控制。

• DOI: 10.1016/j.tet.2010.04.117
• 发表时间: 2010
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Camacho-Davila,Alejandro;Gamage,LalithSR;Wang,Zhipeng;Herndon,JamesW
• 通讯作者: Herndon,JamesW

Direct synthesis of arenecarboxamides through Friedel-Crafts acylation using ureas.

使用脲通过傅克酰化直接合成芳烃酰胺。

• DOI: 10.1016/j.tetlet.2014.06.056
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Ying,Wenjiang;Gamage,LalithSR;Lovro,LukeR;Herndon3rd,JamesW;Jenkins,NathanW;Herndon,JamesW
• 通讯作者: Herndon,JamesW

Total synthesis of (+)-antofine and (-)-cryptopleurine.

• DOI: 10.1002/ejoc.201300200
• 发表时间: 2013-05-01
• 期刊: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 2.8
• 作者: Ying, Weijiang;Herndon, James W.
• 通讯作者: Herndon, James W.