Catalytic Oxidations for Pharmaceutical Synthesis

药物合成的催化氧化

• 批准号: 10797835
• 负责人: Shannon S Stahl
• 金额: $ 15.54万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10797835
• 关键词: 3-Dimensional; Address; Aerobic; Architecture; Area; Carbon; Collaborations; Complement; Coupling; Dedications; Development; Electrodes; Electronics; Ensure; Equipment; Equipment Design; Exhibits; Face; Grant; Kinetics; Mediator; Methods; Modification; Monitor; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Oxidases; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Play; Posttranslational Amino Acid Modification; Process; Production; Reaction; Request for Proposals; Research; Role; Side; System; Therapeutic Agents; Transition Elements; catalyst; cofactor; design; drug discovery; functional group; oxidation

Project Summary Oxidation reactions are among the most important reactions in organic chemistry and play a crucial role in the synthesis of pharmaceuticals, natural products, and other bioactive compounds. Advances in catalytic oxidation reactions have potential for major impact in the discovery and production of pharmaceuticals. The majority of existing catalytic oxidation methods face challenges in their efficiency and selectivity, including chemo-, regio- and stereoselectivity, limiting their use in small- and large-scale applications. The proposed research will develop new oxidation and oxidative coupling methods that form carbon-carbon and carbon- heteroatom bonds, including C(sp3)–H functionalization reactions. Some of the resulting methods will streamline the discovery of new bioactive molecules with diverse three-dimensional architectures, addressing key challenges in medicinal chemistry and drug discovery, while others will provide the basis for streamlined process-scale synthesis of pharmaceuticals. Three complementary project directions are outlined in this proposal. The first focuses on the development of "oxidase"-type aerobic oxidation catalysts that feature a transition metal and a redox active organic co-catalyst. New bioinspired catalyst systems will be explored that exhibit "second-order biomimicry", whereby simple organic precursors undergo oxidative self-processing to create the essential co-catalysts. This process resembles the post-translational modification of amino acid side chains to generate reactive cofactors in Nature. The second project will pursue new electrochemical oxidation methods for the synthesis of organic molecules that are difficult to access via classical synthetic methods. These efforts target the design of mediators and electrocatalysts that permit the reactions to proceed at low electrode potentials, thereby tolerating diverse functional groups and enabling broad scope and utility. Finally, we will develop "radical relay" methods for benzylic C–H oxidation and oxidative coupling to afford new C(sp3) C–O, C–N, C–X, and C–C bonds. These efforts will be applied to pharmaceutical building- block diversification, core-modification, and late-stage functionalization. In each of these project areas, empirical reaction discovery efforts will be complemented by mechanistic studies of the catalytic reactions. Close interactions and collaborations with pharmaceutical companies in all phases of this project will play an important role in ensuring the broadest possible impact of our efforts. Each of these project areas is supported by rigorous kinetic and mechanistic analysis that will greatly benefit from dedicated equipment designed to monitor the reaction progress.

项目摘要 氧化反应是有机化学中最重要的反应之一，在有机合成中起着至关重要的作用。 药物、天然产物和其他生物活性化合物的合成。催化剂研究进展 氧化反应在药物的发现和生产中具有潜在的重大影响。的 大多数现有的催化氧化方法在其效率和选择性方面面临挑战，包括 化学选择性、区域选择性和立体选择性，限制了它们在小规模和大规模应用中的使用。拟议 研究将开发新的氧化和氧化偶联方法，形成碳-碳和碳- 杂原子键，包括C（sp3）-H官能化反应。一些生成的方法将 简化具有不同三维结构的新生物活性分子的发现， 药物化学和药物发现方面的关键挑战，而其他挑战将为简化 药物的工艺规模合成。本报告概述了三个互补的项目方向 提议第一个重点是“氧化酶”型好氧氧化催化剂的发展，其特点是 过渡金属和氧化还原活性有机助催化剂。将探索新的生物启发催化剂系统， 表现出“二级仿生”，即简单的有机前体经历氧化自我加工， 创造必要的助催化剂。这个过程类似于氨基酸的翻译后修饰 侧链产生活性辅因子。第二个项目将追求新的电化学 用于合成有机分子的氧化方法难以通过经典的合成方法获得， 方法.这些努力的目标是设计介体和电催化剂，使反应 在低电极电位下进行，从而容许不同的官能团， 和实用性。最后，我们将开发用于苄基C-H氧化和氧化偶联的“自由基接力”方法 得到新的C（sp3）C-O、C-N、C-X和C-C键。这些努力将应用于制药建设- 嵌段多样化、核修饰和后期官能化。在每一个项目领域， 经验反应发现的努力将由催化反应的机理研究来补充。 在该项目的各个阶段与制药公司的密切互动和合作将发挥重要作用。 在确保我们的努力产生尽可能广泛的影响方面发挥重要作用。每个项目领域都得到支持 通过严格的动力学和机械分析，将大大受益于专用设备， 监测反应进展。

项目成果

Cyclic voltammetry and chronoamperometry: mechanistic tools for organic electrosynthesis

循环伏安法和计时电流法：有机电合成的机械工具

• DOI: 10.1039/d2cs00706a
• 发表时间: 2024
• 期刊: Chemical Society Reviews
• 影响因子: 46.2
• 作者: Rafiee, Mohammad;Abrams, Dylan J.;Cardinale, Luana;Goss, Zachary;Romero-Arenas, Antonio;Stahl, Shannon S.
• 通讯作者: Stahl, Shannon S.

Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas.

• DOI: 10.1039/d1sc02049h
• 发表时间: 2021-08-04
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Suh SE;Nkulu LE;Lin S;Krska SW;Stahl SS
• 通讯作者: Stahl SS

Scalable Flow Electrochemical Alcohol Oxidation: Maintaining High Stereochemical Fidelity in the Synthesis of Levetiracetam.

• DOI: 10.1021/acs.oprd.1c00036
• 发表时间: 2021-12-17
• 期刊: Organic process research & development
• 影响因子: 3.4
• 作者: Zhong X;Hoque MA;Graaf MD;Harper KC;Wang F;Genders JD;Stahl SS
• 通讯作者: Stahl SS

Deriving the Turnover Frequency of Aminoxyl-Catalyzed Alcohol Oxidation by Chronoamperometry: An Introduction to Organic Electrocatalysis.

• DOI: 10.1021/acs.jchemed.0c01244
• 发表时间: 2021-02-09
• 期刊: Journal of chemical education
• 影响因子: 3
• 作者: Goes SL;Mayer MN;Nutting JE;Hoober-Burkhardt LE;Stahl SS;Rafiee M
• 通讯作者: Rafiee M

Exploring Electrosynthesis: Bulk Electrolysis and Cyclic Voltammetry Analysis of the Shono Oxidation.

• DOI: 10.1021/acs.jchemed.2c00221
• 发表时间: 2022-09-13
• 期刊: JOURNAL OF CHEMICAL EDUCATION
• 影响因子: 3
• 作者: Goes, Shannon L.;Nutting, Jordan E.;Hill, Nicholas J.;Stahl, Shannon S.;Rafiee, Mohammad
• 通讯作者: Rafiee, Mohammad