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

Cope重排的新机遇：方法、模块化合成以及在药物发现中的应用

• 批准号: 10625285
• 负责人: Alexander James Grenning
• 金额: $ 35.62万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625285
• 关键词: Address; Biology; Chemicals; Chemistry; Collaborations; Complex; Doctor of Philosophy; Funding; Future; Goals; Histone Deacetylase Inhibitor; Industry; Kinetics; Medicine; Methods; Modernization; Pharmaceutical Chemistry; Play; Postdoctoral Fellow; Publishing; Reaction; Research; Route; Scientist; Thermodynamics; Universities; Variant; Vorinostat; Work; analog; chemical synthesis; coping; drug discovery; improved; interest; programs; student training; unpublished works

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 In our published and unpublished works, we have addressed (or are addressing) fundamental challenges related to thermodynamics and kinetics and proposed potential applications of this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!

研究总结/摘要： Grenning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， 进入药物发现的复杂化学空间。本文总结了工作概述， 旨在将经典的科普重排转化为多功能的合成转化的未来方向 对复杂分子的合成具有很高的价值。虽然科普重排的变体（例如氧-科普 重排、氮杂-科普重排和二乙烯基环丙烷科普重排）已经发现了广泛的 在现代化学合成中的用途和价值，经典的科普已经没有了。这种转变是一个钻石在 粗略地说，后MIRA资助，将对化学合成和药物发现具有明确和多样的价值。在 我们已发表和未发表的作品，我们已经解决（或正在解决）有关的基本挑战 热力学和动力学，并提出了这种转换在模块化复杂的潜在应用 分子合成我们目前和未来的方向将包括继续提高我们对这一点的理解 转换，开发唯一的复杂性生成转换和/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， 对映体富集的结构单元，并制备现代感兴趣的药物发现分子;一个全面的 和多样化的研究计划，侧重于基础和应用化学发现。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合作， 小组，并将继续作出新的连接，允许最有影响力的发现有关的合成 和医药对这一提案的资助将导致价值的新的和普遍的转变， 以及药物发现的新线索例如，我们已经建立了高度模块化的 路线伏立诺他类似物和合作（与Pflum实验室在韦恩州立大学）将检查其 作为HDAC抑制剂。除了化学产品（方法、合成和分子），我们还 要求大量资金用于培训学生和博士后专业合成化学家， 将对知识渊博的科学劳动力至关重要，对各种技术行业都有价值。为 例如，博士我实验室的毕业生目前正在继续他们的博士后研究（例如Primali Navaratne; Stoltz实验室）或直接进入工业（Ehsan Fereyduni;英特尔研究科学家）。 !一个！

项目成果

Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

• DOI: 10.1021/acs.orglett.2c01381
• 发表时间: 2022-05-27
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: De, Subhadip;Tomiczek, Breanna M.;Yang, Yinuo;Ko, Kenneth;Ghiviriga, Ion;Roitberg, Adrian;Grenning, Alexander J.
• 通讯作者: Grenning, Alexander J.

Altered methionine metabolism impacts phenylpropanoid production and plant development in Arabidopsis thaliana.

• DOI: 10.1111/tpj.16370
• 发表时间: 2023-06
• 期刊: The Plant journal : for cell and molecular biology
• 作者: Doosan Shin;Veronica C. Perez;Gabriella K. Dickinson;Haohao Zhao;Ru Dai;Breanna M Tomiczek;K. H. Cho;Ning Zhu;J. Koh;Alexander Grenning;Jeongim Kim

Axially Chiral Cannabinols: A New Platform for Cannabinoid-Inspired Drug Discovery.

• DOI: 10.1002/cmdc.202000025
• 发表时间: 2020-05-06
• 期刊: ChemMedChem
• 影响因子: 3.4

Aromatic Cope rearrangements.

• DOI: 10.1039/d1ob00094b
• 发表时间: 2021-03-21
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2

Construction of vicinal 4°/3°-carbons via reductive Cope rearrangement.

• DOI: 10.1039/d1sc06307c
• 发表时间: 2022-02-16
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Sobie KM;Albritton M;Yang Y;Alves MM;Roitberg A;Grenning AJ
• 通讯作者: Grenning AJ