Cascade Cyclizations for Small Molecule Synthesis

NSF化学部的化学合成计划支持罗切斯特大学化学系的Alison Frontier教授的研究。Frontier教授和她的学生正在开发高效的环化反应，这种反应能够产生致密的多环分子，这是使用其他合成策略难以制备的。这些化学方法可以快速合成复杂的天然和非天然生物活性分子，特别是具有在药物发现工作中有价值的性质的小分子。关于教育活动，正在继续开发一个教育网站(“不是巫毒”)，该网站旨在为在有机化学实验室开始独立研究的学生提供资源。Frontier教授用新的资源丰富了网站，并通过扩展功能来增强访问者的体验。该研究计划包括研究新的阳离子反应性和开发高效和绿色的合成方法。这些项目的重点是将亲核反应与阳离子电环反应相结合的多步反应级联反应，并允许执行高度立体控制的环化反应。这项研究使人们对氢化物移动引发的氧化还原环化反应、与吡啶和呋喃脱芳构化反应耦合的环化反应以及执行更高级别的电环化反应有了更丰富的理解，这些反应几乎都是未知的反应。实现对映体选择性电环化的新策略也在评估中。拟议的研究旨在探索新的反应性和开发有效的、非对映和对映选择性的方法，快速将非环系统转化为桥联、融合或螺环小分子。综合战略是高效和模块化的，通常以环境友好的方式进行。本研究的小分子靶标具有理想的物理化学性质并占据独特的化学空间；这些特征通常与生物活性相关，并满足在药物发现计划中使用的提高化合物收集质量的规定需求。努力还集中在进一步开发非巫毒网站，这是一个每天为数百名有机实验化学家提供服务的资源。

The Chemical Synthesis Program of the NSF Chemistry Division supports the research of Professor Alison Frontier in the Department of Chemistry at the University of Rochester. Professor Frontier and her students are developing highly efficient cyclization reactions which are capable of creating compact polycyclic molecules that are difficult to prepare using other synthetic strategies. These chemical methods enable rapid synthesis of complex natural and non-natural bioactive molecules, especially small molecules with properties demonstrated to be valuable in drug discovery efforts. With respect to educational activities, development continues for an educational website ("Not Voodoo"), which is designed as a resource for students beginning independent research in an organic chemistry laboratory. Professor Frontier enriches the site with new resources, and also enhance the experience of visitors by expanding functionality. The research program involves the study of novel cationic reactivity and the development of efficient and green synthetic methods. The projects focus on multistep reaction cascades that merge nucleophilic reactivity with cationic electrocyclic reactions, and allow the execution of highly stereocontrolled cyclizations. This research is leading to a richer understanding of redox cyclizations which are initiated by hydride shift, cyclizations coupled to pyridine and furan dearomatization, and the execution of higher-order electrocyclizations, which are virtually unknown reactions. New strategies for achieving enantioselective electrocyclization are also being evaluated. The proposed research is directed toward both exploring new reactivity and the development of efficient, diastereo- and enantioselective methods that rapidly transform acyclic systems into bridged, fused, or spirocyclic small molecules. The synthetic strategies are efficient and modular, typically carried out in an environmentally friendly fashion. Small molecule targets of this research have desirable physicochemical properties and occupy unique chemical space; these features often correlate to bioactivity and meet stated needs for improving the quality of compound collections for use in drug discovery programs. Efforts are also focused on further development of the Not Voodoo website, a resource that serves hundreds of organic experimental chemists each day.