Total Synthesis of Bioactive Natural Products

生物活性天然产物的全合成

• 批准号: 7246532
• 负责人: JIN K CHA
• 金额: $ 30.6万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246532
• 关键词: Alkaloids; Analgesics; Anti-Bacterial Agents; Area; Binding; Biological; Biological Factors; Biological Testing; Budgets; Calmodulin; Carboxylic Acids; Complex; Coupling; Development; Diterpenes; Family member; Harringtonines; Imides; Laboratories; Light; Marines; Mediating; Methodology; Methods; Mitomycin; Mitomycins; Nerve Growth Factors; Nicotinic Receptors; Phorbol; Phorbols; Preparation; Property; Range; Reaction; Reporting; Research; Resiniferatoxin; Structure; System; Titanium; antitumor agent; cephalotaxine; cycloaddition; daphnane; fascinate; histrionicotoxins; homoharringtonine; ingenol; inhibitor/antagonist; interest; member; ophiobolins; prostratin; receptor binding; size; tumor

DESCRIPTION (provided by applicant): The proposed study is directed at total syntheses of a wide range of biologically active natural products containing medium-sized carbocycles and heterocycles. The specific aims are the development and applications of general methods or strategies that would allow expedient preparation of structurally complex natural products and synthetic derivatives for biological testing. The synthetic strategies are chosen to provide efficient and stereoselective entries to target compounds in their natural absolute configuration. Toward these objectives, we recently developed two key synthetic methods: (1) diastereoselective [4 + 3] cycloadditions of cyclic oxyallyls and heteroatom-substituted oxyallyls; and (2) Iow-valent titanium-mediated cyclopropanation reactions of carboxylic acid derivatives and related coupling of imides. Among specific target molecules for the next budget period are ingenol (la), as a prominent member of the ingenane, tigliane, and daphnane diterpenes [e.g., other prototypical members of this family include phorbol (lla), prostratin (III), resiniferatoxin (IV)] which possess potent cocarcinogenic, tumor inhibitory, anti-HIV, or analgesic activity; sarains A-C (V-VII), structurally fascinating marine alkaloids, which have been reported to display antitumor, antibacterial, and insecticidal activity; Cephalotaxus alkaloids [e.g., cephalotaxine (VIII) and homoharringtonine (IX)] having significant antileukemic activity; histrionicotoxin (X) which is known to function as a noncompetitive inhibitor of the nicotinic acetylcholine receptors; ophiobolins (Xla-c) which show interesting inhibitory activities of Ca2+-binding calmodulins or angiotension II receptor binding; and erinacines (Xll and XlII), the cyathane-type diterpenoids that possess potent stimulating activity of nerve growth factors; and mitomycin alkaloids [e.g., mitomycin C (XlVc)] which are clinically important antitumor agents.

描述（由申请人提供）：拟议的研究针对多种包含中型碳循环和异环的生物活性天然产物的总合成。具体的目的是一般方法或策略的开发和应用，这些方法或策略将允许为生物测试的结构复杂的天然产物和合成衍生物制备方便制备。选择合成策略以提供有效的立体选择性条目，以在其自然绝对构型中靶向化合物。针对这些目标，我们最近开发了两种关键的合成方法：（1）映射[4 + 3]环状氧气和杂原子取代的羟基的环载； （2）羧酸衍生物的二钛介导的环丙烯反应和伊酰亚基的相关偶联。 Among specific target molecules for the next budget period are ingenol (la), as a prominent member of the ingenane, tigliane, and daphnane diterpenes [e.g., other prototypical members of this family include phorbol (lla), prostratin (III), resiniferatoxin (IV)] which possess potent cocarcinogenic, tumor inhibitory, anti-HIV, or镇痛活性；刺激性A-C（V-VII），结构上令人着迷的海洋生物碱，据报道表现出抗肿瘤，抗菌和杀虫活性；头孢菌素生物碱[例如头孢阿霉素（VIII）和同性恋（ix）]具有显着的抗白血病活性； histrionicotoxin（X）被称为烟碱乙酰胆碱受体的非竞争性抑制剂； Ophiobolins（XLA-C）表现出有趣的Ca2+结合钙调蛋白或血压II受体结合的有趣抑制作用；和Erinacines（XLL和XLII），具有具有有效刺激性神经生长因子活性的甲氧烷类二萜类化合物；和丝裂霉素生物碱[例如丝裂霉素C（XLVC）]，它们是临床上重要的抗肿瘤剂。

项目成果

Olefin Exchange-Mediated Cyclopropanation of Nitriles with Homoallylic Alcohols.

烯烃交换介导的腈与高烯丙醇的环丙烷化。

• DOI: 10.1016/j.tetlet.2008.04.133
• 发表时间: 2008
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Bobrov,DenisN;Kim,Keunho;Cha,JinKun
• 通讯作者: Cha,JinKun

Acid- and Pd(0)-catalyzed ring opening of 1-(1-cycloalkenyl)cyclopropyl sulfonates.

• DOI: 10.1021/ol701653x
• 发表时间: 2007-09
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: L. G. Quan;Hyung Goo Lee;J. Cha

Total synthesis of cyathin A(3) and cyathin B(2).

• DOI: 10.1002/anie.200901669
• 发表时间: 2009
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Kim, Keunho;Cha, Jin Kun
• 通讯作者: Cha, Jin Kun

Synthetic studies toward sarain A. Formation of the western macrocyclic ring.

• DOI: 10.1021/jo026914g
• 发表时间: 2003-02
• 期刊: The Journal of organic chemistry
• 作者: M. Sung;Hyoung Ik Lee;H. Lee;J. Cha

Total synthesis of pareitropone via radical anion coupling.

• DOI: 10.1021/ol1017849
• 发表时间: 2010-09-03
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Hong, Suk-Koo;Kim, Hyeonjeong;Seo, Youngran;Lee, Sang Hyup;Cha, Jin Kun;Kim, Young Gyu
• 通讯作者: Kim, Young Gyu