Macrocyclic Enyne Methathesis and Its Applications

大环烯炔复分解及其应用

• 批准号: 7153483
• 负责人: STEVEN D. BURKE
• 金额: $ 21.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7153483
• 关键词: Address; Alkenes; Alkynes; Anabolism; Area; Biological Factors; C 1027; Classification; Closure; Complex; Condition; Cyclization; Dependency; Development; Effectiveness; Ethers; Ethyl Ether; Facility Construction Funding Category; Goals; Knowledge; Literature; Macrolides; Molecular; Molecular Structure; Nature; Numbers; Object Attachment; Organic Synthesis; Pathway interactions; Pharmacy Schools; Process; Production; Reaction; Research; Silicon; Site; System; Tartrates; Variant; antineoplastic antibiotics; antitumor agent; base; chemical synthesis; combinatorial; design; diene; drug discovery; feeding; mutant; novel strategies; polyketide synthase; professor; research study; size; tartrate; tool

DESCRIPTION (provided by applicant): Specific Aim 1: Development of the Macrocyclic Enyne RCM Reaction a. Accumulation of new knowledge from a systematic study of previously unexplored macrocycle-forming enyne metathesis by developing new general substrate platforms. b. The study of ring size-dependency and substituent effect in the enyne metathesis reaction. c. Exploration of the parameters that control exo/endo-mode in ring-closure and the E/Z selectivity of the resultant cyclic 1,3-dienes. d. Mechanistic study to address one of the controversial issues in enyne metathesis regarding the initiation. Specific Aim 2: Development of a Silicon-tethered Tandem Enyne Metathesis for the Construction of Macrocyclic Carbocycles and Macrolides a. Development of silicon tether strategy for tandem enyne RCM and the efficient synthesis of silyl ethers and silaketals. b. Application of silicon-tethered tandem enyne RCM reaction to a total synthesis of (+)-cochleamycin. Specific Aim 3: Synthesis of Biogenetic Precursors of the Enediyne Core of C-1027 using Macrocyclic Enyne RCM Reaction a. Development of novel strategy based on enyne RCM reaction for the synthesis of enediyne natural products. b. The study of the reactivity and selectivity of the conjugated alkynyl alkylidenes. c. Efficient synthesis of a variety of putative biogenetic precursors of a potent antitumor agent C-1027. d. (Long-term goal) Collaborative research with Professor Ben Shen of School of Pharmacy at UW-Madison by integrating the tools for chemical synthesis and biosynthesis for the elucidation of biosynthetic pathway of enediyne natural product C-1027.

描述（由申请人提供）： 具体目标 1：大环烯炔 RCM 反应的发展 一个。通过开发新的通用底物平台，从对先前未探索的大环形成烯炔复分解的系统研究中积累新知识。 b.烯炔复分解反应中环尺寸依赖性和取代基效应的研究。 c.探索控制闭环中外型/内型模式的参数以及所得环状 1,3-二烯的 E/Z 选择性。 d.机理研究解决烯炔复分解中有关引发的争议问题之一。 具体目标 2：开发用于构建大环碳环和大环内酯的硅系串联烯炔复分解反应 一个。开发串联烯炔 RCM 的硅系链策略以及硅醚和硅缩酮的有效合成。 b.硅系串联烯炔RCM反应在(+)-cochleamycin全合成中的应用 具体目标 3：利用大环烯炔 RCM 反应合成 C-1027 烯二炔核心的生物前体 一个。开发基于烯炔 RCM 反应合成烯二炔天然产物的新策略。 b.共轭炔基亚烷基的反应性和选择性的研究。 c. 有效合成强效抗肿瘤剂 C-1027 的多种假定生物遗传前体。 d. （远期目标）与威斯康辛大学麦迪逊分校药学院Ben Shen教授合作研究，整合化学合成和生物合成工具，阐明烯二炔天然产物C-1027的生物合成途径。