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.

药物市场上近四分之一的顶级药物含有氟;因此，氟在分子中的安装已成为化学家的重要问题。事实上，“荧光屏”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有条不紊地氟化，以提供用于评估的新候选物。因此，一个非常重要的目标是将氟原子置于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，私家侦探，约翰霍普金斯大学的托马斯莱克特卡教授正在开发一种方法，以位点选择性的方式安装氟，这将允许新的和理想的通道，以大的氟化生物活性分子。 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分子（包括天然产物和肽）的氟化作用。这些类型的分子越来越引起化学家的兴趣。 在更广泛的影响方面，Prf。莱克特卡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，至少有一个共同撰写的出版物，作为一个有价值的成就和证书，为进一步研究科学。 Lectka的目标是继续从事少数民族高中学生作为妇女在科学和工程（WISE）计划的一个学期。研究生和高级本科生参加一个由JHU和NSF共同赞助的名为SABES的项目。该计划是由NSF资助的巴尔的摩城市学校和JHU之间的合作，旨在提高STEM学科的教育成果，重点是三个社区的社区参与。约翰霍普金斯大学的托马斯莱克特卡教授正在开发新的光化学方法，重点是现场-选择性氟化以产生通过其他方式不易获得的化学和药学上有趣的产品。应用1涉及使用基于羰基的导向基团（烯酮、酮和二烯酮）来实现对复杂分子的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）作为双链的导向基团。 同样，可预测的选址选择性是最重要的目标。 申请3提出了通过使用相转移催化、刘易斯酸、手性氟化剂以及上述策略的组合来使位点选择性反应具有高度非对映选择性的策略。其特点是使用可见光发光二极管（LED）、廉价的光敏剂和氟化剂，操作简单、相互兼容、条件温和、范围广也是基本目标。特别复杂的分子，包括多环天然产物和肽的双链反应是一个焦点，因为在分子中的单个位点实现和理解双链反应并使其具有非对映选择性。教授Lectka积极参与STEM外展计划，如“科学与工程女性”（WISE）计划和SABES，这是NSF资助的合作，以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）得到了大量投资，因此高度鼓励他们走上STEM领域的道路。这个奖项反映了NSF的法定使命，并通过使用基金会的智力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