STRATEGIC USE OF FURAN IN THE SYNTHESIS OF MOLECULES OF BIOLOGICAL IMPORTANCE

呋喃在具有生物重要性的分子合成中的战略用途

• 批准号: 7721467
• 负责人: Dennis L. Wright
• 金额: $ 0.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721467
• 关键词: Alkenes; Area; Bicyclo Compounds; Biological; Biological Factors; Carbon; Cations; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclization; Ethers; Ethyl Ether; Facility Construction Funding Category; Funding; Furans; Generations; Grant; Institution; Lead; Link; Macrolides; Methodology; Methods; Object Attachment; Octanes; Physical condensation; Placement; Process; Pyrans; Reaction; Research; Research Personnel; Resources; Scheme; Showdomycin; Skeleton; Source; Structure; System; United States National Institutes of Health; Variant; adduct; cycloaddition; cytotoxic; enol; furan; interest; octane; oxidation; programs; viridin C

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our group?s primary focus has been the strategic use of furan in the synthesis of complex molecules of biological importance. We are currently exploring three target-driven methodologies and their application to natural product total synthesis. 1. Electrochemical Furan Annulations: The application of furans as flexible building blocks in synthesis has been an area of ongoing interest in my research group. We have developed a new method for the construction of annulated furans through a key electro-oxidative cyclization. The general strategy begins with a two step annulation reaction that involves a silyl promoted addition of a furyl substituted cuprate to an enone followed by an anodic oxidation to couple the nascent enol ether and the furan. Owing to the diversity of structures available from furan, these intermediates can serve as precursors to a variety on natural product skeletons. We are currently applying this methodology to the synthesis erincacine C and viridin. 2. Synthesis of Pyrans by Ring Opening Cross Metathesis: Another major focus of my program is on the application of ring-opening cross metathesis reactions to bridged bicyclic compounds (Scheme 2). The ready availability of oxabicyclo[3.2.1]octene derivatives from furan makes them powerful building blocks for heterocycle synthesis through ring-opening. Our strategy, utilizing alkene metathesis, links the ring opening with the generation of a new carbon-carbon bond to prepare differentially substituted pyrans. The majority of our studies thus far have focused on the intermolecular cross-metathesis. We have also demonstrated the intramolecular variant of this process that lead to spiro, linear and bridged fused systems depending on placement of the unsaturated tether. We are currently employing these pyran building blocks in the modular construction of the cytotoxic macrolide leucascandrolide. 3. Versatile oxabicyclic building blocks from cyclopropenes: Although oxabicyclo[3.2.1]octane building blocks are typically prepared by Noyori-type cycloadditions between furan and oxyallyl cations, it has been known for decades that analogous systems are available from direct condensation of furan and tetrahalocyclopropenes. While these reactions have been of mechanistic interest, they have remained virtually unexplored from a synthetic perspective. We have used these adducts as direct precursors to various oxabicyclic building blocks, several of which are now available in chiral form. These building blocks are being used as precursors for synthesis of showdomycin and colchicines.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的小组？的主要重点一直是战略性使用呋喃在合成复杂的分子生物学的重要性。我们目前正在探索三个目标驱动的方法及其应用于天然产物的全合成。 1.电化学呋喃环化： 呋喃在合成中作为灵活的结构单元的应用一直是我的研究小组感兴趣的领域。我们开发了一种通过关键的电氧化环化反应来构建环状呋喃的新方法。一般策略开始于两步成环反应，其涉及甲硅烷基促进的呋喃基取代的铜酸酯与烯酮的加成，随后阳极氧化以偶联新生烯醇醚和呋喃。由于呋喃结构的多样性，这些中间体可以作为各种天然产物骨架的前体。我们目前正在应用这种方法合成erincacine C和viridin。 2.通过开环交叉复分解合成吡喃： 我的计划的另一个主要重点是对开环交叉复分解反应的桥接双环化合物（方案2）的应用。氧杂双环[3.2.1]辛烯衍生物的易得性使其成为通过开环合成杂环的强有力的结构单元。我们的策略，利用烯烃复分解，链接开环与新的碳-碳键的产生，以制备差异取代的吡喃。迄今为止，我们的大多数研究都集中在分子间交叉复分解。我们还证明了这一过程的分子内变异，导致螺，线性和桥接的融合系统，这取决于不饱和系链的位置。我们目前正在采用这些吡喃积木的细胞毒性大环内酯leucascandrolide的模块化建设。 3.来自环丙烯的通用氧杂双环结构单元： 尽管氧杂双环[3.2.1]辛烷结构单元通常通过呋喃和氧烯丙基阳离子之间的Noyori型环加成来制备，但几十年来已知类似系统可由呋喃和四卤代环丙烯的直接缩合获得。虽然这些反应一直是机械感兴趣的，但从合成的角度来看，它们实际上仍然未被探索。我们已经使用这些加合物作为各种氧杂双环结构单元的直接前体，其中几种现在可以以手性形式获得。这些结构单元正被用作合成showdomycin和秋水仙碱的前体。