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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们S团队的主要关注点是呋喃在合成具有重要生物学意义的复杂分子中的战略用途。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.电化学呋喃公告： 呋喃在合成中作为柔性构件的应用一直是我的研究小组一直感兴趣的一个领域。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。一般的策略从两步环化反应开始，该反应包括硅基促进的呋喃取代铜酸盐与烯酮的加成，然后是阳极氧化以偶联新生的烯醇醚和呋喃。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。我们目前正在将这一方法应用于马林卡星C和绿豆素的合成。 2.开环交叉复分解合成吡喃： 我项目的另一个主要关注点是开环交叉易位反应在桥联双环化合物中的应用(方案2)。呋喃的草双环[3.2.1]辛烯衍生物的易得性使它们成为通过开环合成杂环的有力构件。我们的策略，利用烯烃复分解，将环的打开与新的碳-碳键的生成联系起来，以制备不同取代的吡喃。到目前为止，我们的大部分研究都集中在分子间的交叉复分解上。我们还展示了这一过程的分子内变体，根据不饱和系链的放置，可以导致螺环、线性和桥接融合系统。我们目前正在使用这些吡喃类构建块来构建细胞毒性大环内酯类化合物。 3.由环丙烯组成的多用途氧双环构造物： 尽管氧杂双环[3.2.1]辛烷构筑块通常是通过呋喃和氧烯丙基阳离子之间的Noyori环加成反应制备的，但几十年来人们已经知道，类似的体系可以通过呋喃和四卤环丙烯的直接缩合来获得。虽然这些反应一直是机械论上的兴趣，但它们实际上仍然没有从合成的角度进行探索。我们已经使用这些加合物作为各种草双环构筑块的直接前体，其中一些现在以手性形式可用。这些积木被用作合成秀多霉素和秋水仙素的前体。

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.