New Catalytic Methods for the Synthesis of Complex Molecules

项目摘要 治疗发展的主要瓶颈之一是快速合成复合物 有机分子来评估生物活性。实现这一目标的最佳手段之一是 下一代治疗剂的发现是铅的晚期功能化（LSF 结构，使得关键性质（KD、log P、PK、PD等）沿着特定生长沿着优化 核心结构的向量。因此，能够改变 通过C-H或C-O在特定脂肪族和芳香族位点上的复合靶分子 键官能化是理想的，以避免从头合成感兴趣的目标。的 这项MIRA赠款的目的是合并两个富有成效的NIGMS资助的项目， 开发新的催化化学转化，立即用于生物医学界 用于复杂有机分子的快速衍生。更具体地说，我们旨在开发新的 通过以下方法官能化脂族C-H键和芳族C-O键的催化方法 使用有效的单电子有机光氧化剂活化有机基质。我们设想 典型的非反应性C-H键的活化可以通过催化的 产生能够选择性夺取H原子的杂原子自由基物质。的 所得到的自由基可以参与许多自由基基团转移反应 共轭加成、卤化、叠氮化和硫代三氟甲基化。我们的目标是 不反应的伯和仲C-H键的杂原子中心的修改 激进的物种重要的是，本文中自由基反应的对映选择性变体将是优选的。 探索，因为这种类型的反应很少。进一步阐述这些激进的 转化将允许级联型反应，其中复杂的手性结构单元可以 可以锻造而不需要对起始材料进行预官能化。的机会 在天然产物合成的级联序列中利用这些自由基转换中的一些 将被利用，如在stemocurtisine的情况下，stemocurtisine是百部生物碱家族的成员。我们 还将继续一个旨在芳香族C-H和C-O键官能化的计划。一种新型 催化古老的亲核芳族取代反应的方法， 作为底物的烷氧基芳烃将允许被胺、氰化物、氟化物和 唑类化合物与作为离核剂的醇盐。这些新开发的转换将 使合成从业者能够使用复杂分子合成的新工具， 治疗发现

Project Summary One of the main bottlenecks to therapeutic development is the rapid synthesis of complex organic molecules to evaluate for bioactivity. One of the best means of accomplishing the discovery of the next generation of therapeutics is the late stage functionalization (LSF) of lead structures, such that key properties (KD, log P, PK, PD, etc) are optimized along specific growth vectors of the core structure. Consequently, synthetic methodologies that are able to modify complex target molecules at specific aliphatic and aromatic sites either through C–H or C–O bond functionalization are ideal so as to avoid de novo synthesis of the target of interest. The aim of this MIRA grant is to merge two productive NIGMS-funded projects that broadly seek to develop new catalytic chemical transformations for immediate use in the biomedical community for rapid derivatization of complex organic molecules. More specifically, we aim to develop new catalytic methods for functionalization of aliphatic C–H bonds and aromatic C–O bonds by activation of organic substrates using potent single electron organic photooxidants. We envision that activation of typically unreactive C–H bonds can be accomplished via the catalytic generation of heteroatom radical species that is capable of selective H-atom abstraction. The resultant radicals can engage in a number of radical group transfer reactions including conjugate addition, halogenation, azidation and thiotrifluoromethylation. We aim to target unreactive primary and secondary C–H bonds by modification of the heteroatom-centered radical species. Importantly, enantioselective variants of the radical reactions herein will be explored, as few reactions of this type are known. Further elaboration of these radical transformations will allow for cascade-type reactions wherein complex chiral building blocks can be forged without the need for prefunctionalization of the starting materials. Opportunities to utilize some of these radical transformations in cascade sequences for natural product synthesis will be exploited, as in the case of stemocurtisine, a member of the stemona alkaloid family. We also will continue a program aimed at aromatic C–H and C–O bond functionalization. A novel method for catalysis of the venerable nucleophilic aromatic substitution reaction using alkoxyarenes as substrates will allow for direct substitution by amines, cyanide, fluoride and azoles with the alkoxide acting as the nucleofuge. These newly developed transformations will enable synthetic practitioners with new tools for complex molecule synthesis aimed at therapeutic discovery.