Synthesis of Bioactive Small Molecule Building Blocks

项目摘要 创造下一代小分子治疗剂的一个重大障碍是缺乏通用的药物组合物。 以及获得某些含有官能团的立体化学致密结构的有效方法 对生物活性很重要。本申请旨在继续一个富有成效的MIRA计划有关的 手性、功能化生物活性小分子结构单元的实验室制备。总目标 该计划是开发新的合成化学平台，使快速和选择性的 构建与生物医学应用直接相关的新结构。 我们在下一个项目期间寻求解决的主要挑战包括： ·对映聚合反应：一般策略和反应平台的显著扩展， 将容易获得的外消旋起始原料催化转化为高价值的对映异构体 浓缩产品; ·盐基催化：开发广泛的新催化模式，通过准分子操作， 通过离子束缚实现的分子内机制; ·原料芳烃的脱芳构化：有用的氧化脱芳构化反应的开发 其将容易获得芳族结构单元转化为官能化的对映体纯的结构单元 块; 天然产物合成：复杂天然产物的高效合成和生物学评价 和新的结构类似物。 总的来说，我们预计这些MIRA研究活动将提供轻松访问以前的结构的机会 迄今为止未知的或只能通过效率低下和/或不切实际的方法才能获得的。的 该计划以新反应和催化剂的形式产生新的化学知识，供科学家使用。 社区，也为我们提供了新的化学物质，以研究与我们的生物合作者的问题， 生物医学相关性。

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.