New Approaches to Site-Selective Fluorination

位点选择性氟化的新方法

基本信息

批准号：
1800510
负责人：
Thomas Lectka
金额：
$ 46万
依托单位：
Johns Hopkins University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1800510&HistoricalAwards=false
关键词：
New Approaches Site Selective Fluorination

项目摘要

Nearly one fourth of the top pharmaceuticals on the drug market contain fluorine; thus the installation of fluorine in molecules has become an important problem for chemists. In fact, "fluorination screens" have become commonplace in pharmaceutical chemistry. In this method, molecules are fluorinated methodically at each and every accessible site to render new candidates for evaluation. Thus, one very important goal is to place fluorine atoms in very precise positions within complex molecules - in short, achieving "site selectivity." In this project, the P.I., Prof. Thomas Lectka of Johns Hopkins University, is developing methods to install fluorine in a site selective manner that would allow new and desirable passageways to large fluorinated bioactive molecules. Simple reaction conditions, safety, and ease of use are important goals as well. The fluorination of especially complex molecules, including natural products and peptides, is highlighted. These types of molecules are becoming of ever more interest to chemists. In terms of broader impacts, Prf. Lectka has fostered a research group that contains predominately undergraduates. The majority of these students leave the lab with at least one co-authored publication that serves as a valuable accomplishment and credential for further studies in science. Prof. Lectka aims to continue to engage minority high school students as part of the Women in Science and Engineering (WISE) program for a semester. Graduate students and advanced undergrads participate in a program cosponsored by JHU and the NSF called SABES. This program is an NSF-funded collaboration between Baltimore City Schools and JHU and aims to improve educational outcomes in STEM disciplines with a focus on community engagement in three neighborhoods.With funding from the Synthesis Program of the Chemistry Division, Prof. Thomas Lectka of Johns Hopkins University is developing new photochemical methods focused on site-selective fluorination to produce chemically and pharmaceutically interesting products not easily accessible by other means. Application 1 involves the use of carbonyl-based directing groups (enones, ketones, and dienones) to achieve predictable site-selectivity on complex molecules. Application 2 involves carboxylic acid derivatives (amides, lactams, and lactones) as directing groups for fluorination. Once again, predictable site-selectivity is the paramount goal. Application 3 is addressing strategies to render the site-selective reactions highly diastereoselective through the use of phase transfer catalysis, Lewis acids, chiral fluorinating agents, and a combination of the aforementioned strategies. The use of visible light-emitting diodes (LEDs), cheap photosensitizers and fluorinating agents is featured, and operational simplicity, mutual compatibility, mild conditions, and broad scope are fundamental goals as well. The fluorination of especially complex molecules, including polycyclic natural products and peptides is a focus as is achieving and understanding fluorination at a single site in a molecule and rendering it diastereoselective. Prof. Lectka is heavily involved in the STEM outreach programs such as the "Women in Science and Engineering" (WISE) Program, and SABES, which is an NSF-funded collaboration to improve educational outcomes in the Baltimore City Public Schools. In this research group, undergraduates (including members of many underrepresented groups) are heavily invested and are thus highly encouraged to follow a path into STEM fields.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

药品市场上近四分之一的顶级药品都含有氟；因此，氟在分子中的安装已成为化学家们面临的一个重要问题。事实上，“氟化筛选”在药物化学中已经变得司空见惯。在这种方法中，分子在每个可接近的位点被系统地氟化，以提供新的候选物进行评估。因此，一个非常重要的目标是将氟原子放置在复杂分子内非常精确的位置 - 简而言之，实现“位点选择性”。在这个项目中，约翰·霍普金斯大学的托马斯·莱克特卡教授正在开发一种以位点选择性方式安装氟的方法，这将为大型氟化生物活性分子提供新的、理想的通道。简单的反应条件、安全性和易用性也是重要的目标。重点介绍了特别复杂的分子（包括天然产物和肽）的氟化。化学家对这些类型的分子越来越感兴趣。就更广泛的影响而言，Prf。莱克卡组建了一个主要由本科生组成的研究小组。这些学生中的大多数在离开实验室时至少持有一份共同撰写的出版物，作为进一步科学研究的宝贵成就和凭证。 Lectka 教授的目标是继续让少数族裔高中生参与一个学期的科学与工程女性 (WISE) 项目。研究生和高年级本科生参加由 JHU 和 NSF 共同发起的名为 SABES 的项目。该项目是巴尔的摩城市学校和约翰霍普金斯大学之间由 NSF 资助的合作项目，旨在提高 STEM 学科的教育成果，重点关注三个社区的社区参与。在化学部综合项目的资助下，约翰斯大学的 Thomas Lectka 教授霍普金斯大学正在开发新的光化学方法，重点是位点选择性氟化，以生产其他方法不易获得的具有化学和药学意义的产品。应用 1 涉及使用基于羰基的导向基团（烯酮、酮和二烯酮）来实现复杂分子的可预测位点选择性。应用2涉及羧酸衍生物（酰胺、内酰胺和内酯）作为氟化的导向基团。再次强调，可预测的位点选择性是最重要的目标。应用3提出了通过使用相转移催化、路易斯酸、手性氟化剂以及上述策略的组合使位点选择性反应具有高度非对映选择性的策略。以使用可见光发光二极管（LED）、廉价的光敏剂和氟化剂为特色，操作简单、相互兼容、条件温和、适用范围广泛也是基本目标。特别复杂的分子（包括多环天然产物和肽）的氟化是一个焦点，因为实现和理解分子中单个位点的氟化并使其具有非对映选择性。 Lectka 教授积极参与 STEM 推广计划，例如“科学与工程领域的女性”(WISE) 计划和 SABES（这是一项由 NSF 资助的合作项目，旨在改善巴尔的摩市公立学校的教育成果）。在这个研究小组中，本科生（包括许多代表性不足群体的成员）得到了大量投资，因此被强烈鼓励进入 STEM 领域。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优势进行评估，被认为值得支持以及更广泛的影响审查标准。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Arene Amination Instead of Fluorination: Substitution Pattern Governs the Reactivity of Dialkoxybenzenes with Selectfluor

DOI：
10.1021/acs.joc.1c00231
发表时间：
2021-03-31
期刊：
JOURNAL OF ORGANIC CHEMISTRY
影响因子：
3.6
作者：
Capilato, Joseph N.;Lectka, Thomas
通讯作者：
Lectka, Thomas

Discovery and Mechanistic Study of a Totally Organic C (aryl) –C (alkyl) Oxygen Insertion Reaction

全有机C（芳基）→C（烷基）氧插入反应的发现及机理研究

DOI：
10.1021/acs.joc.9b02238
发表时间：
2019
期刊：
The Journal of Organic Chemistry
影响因子：
0
作者：
Kazim, Muhammad;Foy, Hayden;Siegler, Maxime A.;Dudding, Travis;Lectka, Thomas
通讯作者：
Lectka, Thomas

Energy- and conformer-dependent excited-state relaxation of an E / Z photoswitchable thienyl-ethene

E / Z光可切换噻吩基乙烯的能量和构象异构体依赖性激发态弛豫

DOI：
10.1039/c9cp01226e
发表时间：
2019
期刊：
Physical Chemistry Chemical Physics
影响因子：
3.3
作者：
Young, Jamie D.;Honick, Chana R.;Zhou, Jiawang;Pitts, Cody R.;Ghorbani, Fereshte;Peters, Garvin M.;Lectka, Thomas;Tovar, John D.;Bragg, Arthur E.
通讯作者：
Bragg, Arthur E.

A Protonated Quinone Methide Stabilized by a Combination of Partial Aromatization and π-Interaction: Spectroscopic and Crystallographic Analysis

通过部分芳构化和γ-相互作用相结合稳定质子化醌甲基化物：光谱和晶体分析