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复合体的快速合成 用于评估生物活性的有机分子。实现这一目标的最好方法之一 新一代疗法的发现是铅的晚期功能化(LSF) 结构，使得关键属性(Kd、logP、Pk、Pd等)沿着特定的生长被优化 核心结构的矢量。因此，能够修改的合成方法 通过C-H或C-O在特定脂肪族和芳香族位置上的复杂靶分子 键功能化是理想的，以避免目标的从头合成。这个 这笔Mira赠款的目的是合并两个由NIGMS资助的生产性项目，这两个项目广泛寻求 开发新的催化化学转化方法，立即用于生物医学界 用于复杂有机分子的快速衍生化。更具体地说，我们的目标是开发新的 脂肪族C-H键和芳香族C-O键功能化的催化方法 使用有效的单电子有机光氧化剂激活有机底物。我们设想 通常无活性的C-H键的活化可以通过催化剂完成 生成能够选择性提取氢原子的杂原子自由基物种。这个 生成的自由基可以参与许多自由基转移反应，包括 共轭加成、卤化、叠氮化和硫代三氟甲基化。我们的目标是 以杂原子为中心修饰不反应的伯次C-H键 激进物种。重要的是，这里的自由基反应的对映选择性变体将是 探索，因为这种类型的反应很少为人所知。对这些部首的进一步阐述 转换将允许级联类型的反应，其中复杂的手性构建块可以 无需对起始材料进行预功能化处理即可锻造。获得以下机会 在级联序列中利用这些自由基转换中的一些来合成天然产物 将会被开发，就像是茎生物碱家族的一员--球茎草碱。我们 还将继续一个旨在芳香族C-H和C-O键功能化的计划。一本小说 一种古老的亲核芳香族取代反应的催化方法 烷氧基芳烃作为底物将允许胺、氰化物、氟化物和 烷氧基作为核隔离剂的唑类化合物。这些新开发的转变将 为合成从业者提供用于复杂分子合成的新工具 治疗方面的发现。

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.