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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们小组的主要重点是在具有生物重要性的复杂分子的合成中战略性地使用呋喃。我们目前正在探索三种目标驱动的方法及其在天然产物全合成中的应用。 1.电化学呋喃环： 呋喃作为合成中的灵活构件的应用一直是我的研究小组持续感兴趣的领域。我们开发了一种通过关键的电氧化环化构建环状呋喃的新方法。一般策略从两步成环反应开始，其中涉及甲硅烷基促进的呋喃基取代的铜酸酯与烯酮的加成，然后进行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多种天然产物骨架的前体。我们目前正在将此方法应用于合成 erincacine C 和 viridin。 2. 开环交叉复分解合成吡喃： 我的项目的另一个主要重点是开环交叉复分解反应在桥联双环化合物中的应用（方案 2）。来自呋喃的氧杂双环[3.2.1]辛烯衍生物的现成性使其成为通过开环合成杂环的强大构建单元。我们的策略利用烯烃复分解，将开环与新碳-碳键的生成联系起来，以制备差异取代的吡喃。迄今为止，我们的大部分研究都集中在分子间交叉复分解上。我们还证明了该过程的分子内变体，根据不饱和系链的位置，可产生螺旋、线性和桥接融合系统。我们目前正在将这些吡喃结构单元用于细胞毒性大环内酯 leucascandrolide 的模块化构建。 3. 来自环丙烯的多功能氧双环结构单元： 虽然氧杂二环[3.2.1]辛烷结构单元通常是通过呋喃和氧烯丙基阳离子之间的Noyori型环加成来制备的，但几十年来人们已经知道，可以通过呋喃和四卤代环丙烯的直接缩合获得类似的系统。虽然这些反应引起了机械学的兴趣，但从综合的角度来看，它们实际上仍未被探索。我们已经使用这些加合物作为各种氧双环结构单元的直接前体，其中一些现在可以手性形式提供。这些结构单元被用作合成秀多霉素和秋水仙碱的前体。