New opportunities for the Cope rearrangement: methods, modular synthesis, and applications in drug discovery

研究摘要/摘要： 格勒宁研究实验室的总体目标是开发可编程和高度多样化的平台，以 访问对药物发现感兴趣的复杂化学空间。这里总结的是工作概述和 旨在将经典的Cope重排转化为多功能合成转化的未来方向 对于复杂分子的合成具有很高的应用价值。而COPE重排的变体(例如氧合-COPE 重排、氮杂-钴重排和二乙烯基环丙烷钴重排)发现了广泛的 在现代化学合成中的用途和价值，经典的科普是没有的。这种转变是世界上的一颗钻石 粗略地说，后Mira资助将对化学合成和药物发现具有明显和多样化的价值。在……里面 我们已出版和未出版的作品，我们已经解决(或正在解决)与 对热力学和动力学的影响，并提出了这种变换在模数络合物中的潜在应用 分子合成。我们当前和未来的方向将包括继续提高对这一点的认识 转换，开发独特、复杂的转换和/或序列，其中 转化起着关键作用，介绍了多种催化-不对称方法获取 富含对映体的构建单元，并制备现代药物发现感兴趣的分子；全面的 以及多样化的研究计划，重点放在基础和应用化学发现上。关于 后一个目标，我们目前正在与许多药物化学和化学生物学进行合作 并将继续建立新的联系，以实现与合成相关的最有影响力的发现 还有医学。对这项提议的资助将导致超出范围的新的和一般的价值转变 关于这项提议和药物发现的新线索。例如，我们已经建立了高度模块化的 与韦恩州立大学的Pflum实验室合作)将检查他们的 作为HDAC抑制剂的生物活性。超越或化学产品(方法、合成和分子)，我们是 要求提供大量资金，用于培训专业合成化学家的学生和博士后 将对知识渊博、科学的劳动力队伍具有关键价值，对各种技术行业也有价值。为 例如，我实验室的博士毕业生目前正在继续他们的博士后研究(例如PriMali Navaratne； 斯托尔茨实验室)或直接进入工业(Ehsan Fereyduni；英特尔研究科学家)。 ！1！

Research Summary/Abstract: The overall goal of the Grenning research lab is to develop programable and highly diversifiable platforms for accessing complex chemical space of interest to drug discovery. Summarized herein is an overview of work and future directions aimed at transforming the classic Cope rearrangement into a versatile synthetic transformation of high value for complex molecule synthesis. While variants of the Cope rearrangement (e.g. the oxy-Cope rearrangement, aza-Cope rearrangement, and divinylcyclopropane Cope rearrangement) have found extensive use and value in modern chemical synthesis, the classic Cope has not. This transformation is a diamond in the rough that, post-MIRA funding, will have clear and diverse value to chemical synthesis and drug discovery. In our published and unpublished works, we have addressed (or are addressing) fundamental challenges related to thermodynamics and kinetics and proposed potential applications of this transformation in modular complex molecule synthesis. Our current and future directions will involve continuing to improve our understanding of this transformation, develop unique, complexity generating transformations and/or sequences where this transformation plays a key role, introduce a variety of catalytic-asymmetric methods for accessing enantioenriched building blocks, and prepare molecules of modern interest to drug discovery; a well-rounded and diverse research program focusing both on fundamental and applied chemical discoveries. Regarding the latter goal, we currently have on going collaborations with many medicinal chemistry and chemical biology groups and will continue to make new connections allowing for the most impactful discoveries related to synthesis and medicine. Funding of this proposal will result in new and general transformations of value beyond the scope of the proposal and new leads for drug discovery. For example, we have already established a highly modular route to Vorinostat analogs and collaboratively (with the Pflum lab at Wayne State University) will examine their bioactivity as HDAC inhibitors. Beyond or chemistry products (methods, syntheses, and molecules), we are requesting significant funding for the training of students and postdocs to professional synthetic chemists which will be of critical value to a knowledgeable, scientific workforce of value to a variety of technical industries. For example, Ph.D. graduates from my lab are currently continuing their studies as post docs (e.g. Primali Navaratne; Stoltz Lab) or have gone directly into industry (Ehsan Fereyduni; Research Scientist at Intel). ! 1!