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.

项目摘要/摘要概括该研究计划的总体目标是开发分析，工具和方法，以实现新的，更有效的试剂，催化剂和生物配体。一个重点将放在最新的计算方法上，以了解立体选择性，化学选择性，和分子水平的反应性，目的是设计新的，更有效的试剂，催化剂和生物配体。选择性和反应性的控制是有效合成的重要特征，但是我们分子水平的理解基本相互作用如何扰动这些方面只是基本的。此外，这些相同基本互动如何控制生物环境中的约束的许多方面是不完全理解。另一个重点将是通过C-C，C-O和C-N键形成碎片的氧化耦合 C – H激活化学。催化剂库将设计用于研究仿生反应原理：1）将催化剂氧化电位与底物的氧化电位匹配考虑和2）选择可以利用氧气再生催化物种的金属。这些图书馆将以高通量显微镜格式部署，以发现迄今未想象的反应性模式。从获得的数据中，将构建反应“曲线”，以及有关反应性，选择性，和机制将进行，将通过实验进行测试。该提案的基本标志是能够访问新的反应模式来构建重要有机结构以有效和理性的方式。计算和机械理解使我们解决问题和假设的工具。高吞吐量显微镜实验允许有理要广泛审问的假设，并促进优化许多相互依存的变量可能的反应空间。关联该提案的基本标志是通过计算设计新反应和催化剂的能力和机械研究。目标是以有效和理性的方式构建重要的有机结构。新的合成方法大大增加了获得未开发的化学空间的机会，导致材料和受益于社会的药物。为了实现这一目标，调查将集中于获得改进的理解反应性和选择性。新的氧化耦合化学的发展是一种特殊的由于较低的步骤计数和较小的废物流的效率提高而引起的重点。挑战由于典型有机分子中存在的许多C – H键，因此在任何给定转化中的选择性是选择性。仿生过程的使用导致生物活性天然产品和类似天然产物的核心，理想的实体在工业环境之外吸收的宝贵培训将得到毕业。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

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.

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.

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