Computation and Development of New, Enabling Synthetic Methods

新的、可行的合成方法的计算和开发

基本信息

批准号：
10624435
负责人：
Marisa C Kozlowski
金额：
$ 54.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Summary The overall objective of this research program is to develop analyses, tools, and methods to achieve new, more effective reagents, catalysts, and biological ligands. One focus will be on state-of-the-art computation methods to understand stereoselectivity, chemoselectivity, and reactivity at the molecular level with the aim of designing new, more effective reagents, catalysts, and biological ligands. The control of selectivity and reactivity are essential features of efficient synthesis, yet our molecular level understanding of how fundamental interactions perturb these aspects is only rudimentary. Further, many aspects of how these same fundamental interactions govern binding in a biological context are incompletely understood. Another focus will be on oxidative coupling of fragments via C-C, C-O, and C-N bond formation by means of C–H activation chemistry. Catalyst libraries will be designed for study of biomimetic reactions using two guiding principles: 1) matching catalyst oxidation potentials with the oxidation potentials of the substrates under consideration and 2) selecting metals that can utilize oxygen to regenerate the catalytic species. These libraries will be deployed in a high-throughput microscale format to discover reactivity patterns heretofore unimagined. From the data obtained, reaction “profiles” will be constructed and new inferences about reactivity, selectivity, and mechanism will be made, which will be tested experimentally. The fundamental hallmark of this proposal is the ability to access new reaction patterns to construct important organic structures in an efficient and rational manner. Computation and mechanistic understanding gives us the tools to solve problems and posit hypotheses. High throughput microscale experimentation permits rational hypotheses to be interrogated broadly and to facilitate optimization of the many interdependent variables in the possible reaction space. Relevance The fundamental hallmark of this proposal is the ability to design new reactions and catalysts via computation and mechanistic study. The goal is to construct important organic structures in an efficient and rational manner. New synthetic methods greatly increase access to untapped chemical space, leading to materials and pharmaceuticals that benefit society. To achieve this goal, investigations will focus on obtaining an improved understanding of reactivity and selectivity. The development of new oxidative coupling chemistry is a particular focus due to increases in efficiency from lower step counts and smaller waste streams. The challenge in this area is selectivity in any given transformation due the numerous C–H bonds present in a typical organic molecule. Use of biomimetic processes leads to bioactive natural products and natural product-like cores, desirable entities in medicinal chemistry. Invaluable training, absent outside of industrial settings, will be afforded to graduate students and other coworkers.

项目概要/摘要概括该研究计划的总体目标是开发分析、工具和方法来实现新的、更有效的试剂、催化剂和生物配体。重点将放在最先进的计算方法上，以了解立体选择性、化学选择性、和分子水平的反应性，旨在设计新的、更有效的试剂、催化剂和生物配体的选择性和反应性的控制是有效合成的基本特征，然而我们的对基本相互作用如何扰乱这些方面的分子水平理解还只是初步的。此外，这些相同的基本相互作用如何在生物背景下控制结合的许多方面是不完全理解。另一个重点是通过 C-C、C-O 和 C-N 键形成的片段氧化偶联： C-H 活化化学将被设计用于使用两种引导的仿生反应的研究。原则：1）使催化剂氧化电位与底物氧化电位相匹配考虑和2)选择可以利用氧气再生催化物质的金属。将以高通量微尺度形式部署，以发现迄今为止无法想象的反应模式。根据获得的数据，将构建反应“曲线”并得出有关反应性、选择性、并将制作机制，并进行实验测试。该提案的基本特点是能够获得新的反应模式来构建重要的反应模式。以有效和合理的方式计算和机械理解为我们提供了有机结构。解决问题和提出假设的工具高通量微型实验允许理性。假设被广泛质疑，并促进许多相互依赖的变量的优化可能的反应空间。关联该提案的基本特点是能够通过计算设计新的反应和催化剂和机制研究的目标是以有效和合理的方式构建重要的有机结构。新的合成方法大大增加了对未开发化学空间的利用，从而产生材料和为了实现这一目标，研究的重点是获得改进的药物。对反应性和选择性的理解是一种特殊的氧化偶联化学的发展。由于步数减少和废物流减少而提高了效率，因此成为焦点。由于典型有机分子中存在大量 C-H 键，面积是任何给定转化中的选择性。使用仿生工艺可产生具有生物活性的天然产物和类似天然产物的核心、理想的实体毕业时将获得工业环境之外缺乏的宝贵培训。学生和其他同事。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biomolecule-Compatible Dehydrogenative Chan-Lam Coupling of Free Sulfilimines.

DOI：
10.1021/jacs.2c04627
发表时间：
2022-07-13
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Meng, Tingting;Wells, Lucille A.;Wang, Tianxin;Wang, Jinyu;Zhang, Shishuo;Wang, Jie;Kozlowski, Marisa C.;Jia, Tiezheng
通讯作者：
Jia, Tiezheng

Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products

DOI：
10.1021/acs.orglett.0c00577
发表时间：
2020-04-17
期刊：
ORGANIC LETTERS
影响因子：
5.2
作者：
Gilmartin, Philip H.;Kozlowski, Marisa C.
通讯作者：
Kozlowski, Marisa C.

A Bisphenolic Honokiol Analog Outcompetes Oral Antimicrobial Agent Cetylpyridinium Chloride via a Membrane-Associated Mechanism

DOI：
10.1021/acsinfecdis.9b00190
发表时间：
2020-01-01
期刊：
ACS INFECTIOUS DISEASES
影响因子：
5.3
作者：
Ochoa, Cristian;Solinski, Amy E.;Kozlowski, Marisa C.
通讯作者：
Kozlowski, Marisa C.

Modification of Biphenolic Anti-Bacterial to Achieve Broad-Spectrum Activity.

DOI：
10.1002/cmdc.202100783
发表时间：
2022-05-04
期刊：
ChemMedChem
影响因子：
3.4
作者：
通讯作者：

Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

通过快速比色评估氢键参数：评估生物配体和有机催化剂中的结构成分。

DOI：
10.1002/chem.202300696
发表时间：
2023
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Roenfanz,HannaF;Paniak,ThomasJ;Berlin,CameronB;Tran,Van;Francisco,KarolR;Lassalas,Pierrik;Devas,Anisha;Landes,Olivia;Rosenberger,Avalon;Rotella,MadelineE;Ballatore,Carlo;Kozlowski,MarisaC
通讯作者：
Kozlowski,MarisaC