Synthesis of Bioactive Small Molecule Building Blocks

项目摘要 创建下一代小分子疗法的一个重大障碍是缺乏通用的 以及用于访问包含功能的某些立体化学致密结构的有效方法 对生物活性很重要。此应用程序寻求继续与以下方面有关的生产性Mira计划 手性、功能化生物活性小分子构建块的实验室制备。的总目标是 这项计划是为了开发新的合成化学平台，使之能够快速和选择性地 构建与生物医学应用直接相关的新结构。 在接下来的项目期内，我们寻求解决的主要挑战包括： ·对映体会聚反应：对一般策略和反应平台的显著扩展 催化将易得的外消旋原料对映体转化为高价值的 丰富的产品； ·盐基催化：发展广泛的新催化模式，这些模式由准 离子拴系所致的分子内机制； ·原料芳烃的脱芳构化：开发有用的氧化脱芳构化反应 将现成芳香族建筑材料转化为功能化的纯对映体建筑 区块； ·天然产物合成：复杂天然产物的高效合成和生物学评价 和新的结构类比。 总体而言，我们期待着这些米拉研究活动将提供对曾经是 迄今为止不为人所知或只能依靠低效和/或不切实际的方法才能获得。这个 计划以新反应和催化剂的形式产生新的化学知识，供科学工作者使用 也为我们提供了新的化学物质，供我们与生物合作者就问题进行研究 与生物医学相关。

Project Summary A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This application seeks to continue a productive MIRA program concerned with the laboratory preparation of chiral, functionalized bioactive small molecule building blocks. The general goal of this program is to develop new synthetic chemistry platforms that will enable the rapid and selective construction of new structures of immediate relevance for biomedical applications. Key challenges that we seek to address in the coming project period include: • Enantioconvergent reactions: A significant expansion of general strategies and reaction platforms that catalytically convert readily accessible racemic starting materials into high value, enantiomerically enriched products; • Salt-based catalysis: The development of broad new catalysis modes that operate by quasi- intramolecular mechanisms enabled by ionic tethering; • Dearomatization of feedstock arenes: The development of useful oxidative dearomatization reactions that convert readily available aromatic building blocks into functionalized enantiomerically pure building blocks; • Natural product synthesis: The efficient synthesis and biological evaluation of complex natural products and new structural analogs. Collectively, we expect that these MIRA research activities will provide facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical. The program generates new chemical knowledge in the form of new reactions and catalysts for use by the scientific community, and also provides new chemical matter for us to study with our biological collaborators on problems of biomedical relevance.