New Approaches to Site-Selective Fluorination

位点选择性氟化的新方法

• 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

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含有氟；因此，氟在分子中的安装就成为化学家的一个重要问题。事实上，“氟化筛”在药物化学中已经司空见惯。在这种方法中，分子在每个可访问的位点都有系统地氟化，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中非常精确的位置-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P.I托马斯·莱克卡教授正在开发一种方法，以一种选择性的方式安装氟，这将为大的含氟生物活性分子提供新的和理想的通道。简单的反应条件、安全性和易用性也是重要的目标。特别复杂的分子，包括天然产物和肽的氟化，是突出。化学家们对这类分子越来越感兴趣。就更广泛的影响而言。Lectka培养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离开实验室时，至少有一篇合著的出版物，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学生参与一个学期的女性科学与工程（WISE）项目。研究生和高级本科生参加一个由JHU和NSF共同发起的名为SABES的项目。该项目由美国国家科学基金会（nsf）资助，由巴尔的摩市学校和JHU合作开展，旨在改善STEM学科的教育成果，重点关注三个社区的社区参与。在化学部合成项目的资助下，约翰霍普金斯大学的Thomas Lectka教授正在开发新的光化学方法，重点是位点选择性氟化，以生产化学和药学上有趣的产品，这些产品不易通过其他方法获得。应用1涉及使用羰基导向基团（烯酮、酮和二烯酮）在复杂分子上实现可预测的位点选择性。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。再一次，可预测的站点选择性是最重要的目标。应用3通过使用相转移催化、路易斯酸、手性氟化剂和上述策略的组合，解决了使位点选择性反应具有高度非对映选择性的策略。使用可见发光二极管（led）、廉价光敏剂和氟化剂是其特点，操作简单、相互兼容、条件温和、适用范围广是其基本目标。包括多环天然产物和多肽在内的特别复杂分子的氟化是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的一个重点。Lectka教授积极参与STEM外展项目，如“女性参与科学与工程”（WISE）项目和SABES，这是一项由美国国家科学基金会资助的合作项目，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的群体的成员）投入了大量资金，因此高度鼓励他们进入STEM领域。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

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
• 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

• DOI: 10.1021/acs.joc.9b00923
• 发表时间: 2019
• 期刊: The Journal of Organic Chemistry
• 作者: Kazim, Muhammad;Siegler, Maxime A.;Lectka, Thomas
• 通讯作者: Lectka, Thomas

Synthesis and X-Ray crystallography of a substituted trityl fluoride: Ordering power of a C-F bond

取代三苯甲基氟的合成和 X 射线晶体学：C-F 键的有序能力

• DOI: 10.1016/j.jfluchem.2019.109377
• 发表时间: 2019
• 期刊: Journal of Fluorine Chemistry
• 影响因子: 1.9
• 作者: York, Gabriel D.;Siegler, Maxime A.;Patel, Dhaval D.;Lectka, Thomas
• 通讯作者: Lectka, Thomas