New Catalytic Methods for the Synthesis of Complex Molecules

合成复杂分子的新催化方法

基本信息

批准号：
10395487
负责人：
David A Nicewicz
金额：
$ 55.89万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

项目摘要

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.

项目摘要热发展的主要瓶颈之一是复杂的快速合成有机分子评估生物活性。实现的最佳手段之一下一代理论的发现是铅的后期功能化（LSF）结构，使关键属性（KD，Log P，PK，PD等）沿特定的增长进行了优化核心结构的向量。因此，能够修改的合成方法通过C – H或C – O的特定脂肪族和芳香族位点的复杂靶分子键功能是理想的选择，以避免从头综合感兴趣的目标。这这项MIRA赠款的目的是合并两个富有生产力的NIGMS资助的项目，这些项目广泛寻求开发新的催化化学转化，以立即在生物医学界使用为了快速衍生化的有机分子。更具体地说，我们旨在开发新的脂肪族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激活有机底物。我们设想通常可以通过催化来实现通常不反应的C – H键的激活能够选择性H原子抽象的杂原自由基产生。这由此导致的自由基可以参与许多激进的群体转移反应共轭添加，卤代化，氮化和硫氟甲基化。我们的目标是针对通过修改杂原子以杂原子为中心激进物种。重要的是，这里的激进反应的对映选择性变体将是经过探索，因为这种类型的反应很少。进一步阐述这些激进的转换将允许级联型反应，其中复杂的手性构建块可以忘记了起始材料的无需预官能化。机会利用级联序列中的一些自由基转换进行天然产物合成将被探讨，就像Stemocurtisine一样，是Stemona生物碱家族的成员。我们还将继续一个针对芳族C – H和C – O键功能化的程序。小说使用使用的核整体芳族芳族取代反应的方法烷氧基烯作为底物将允许胺，氰化物，氟化物和烷氧化氮的唑，充当核对象。这些新开发的转型将使用新工具启用合成从业者，用于复杂分子合成治疗发现。