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中有氟；因此，在分子中的氟安装已成为化学家的重要问题。实际上，“氟化筛选”在药物化学中已成为司空见惯。在这种方法中，分子在每个可访问的位点有条不紊地进行氟化，以使新的候选者进行评估。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“位置选择性”。 在这个项目中，约翰·霍普金斯大学的P.I.，P.I.，托马斯·莱克特卡（Thomas Lectka）教授正在开发以现场选择的方式安装氟的方法，这些方法将允许新的且理想的通道到大型氟化生物活性分子。 简单的反应条件，安全性和易用性也是重要目标。 突出显示了特别复杂的分子（包括天然产物和肽）的氟化。这些类型的分子变得越来越引起化学家的兴趣。 在更广泛的影响方面，PRF。 Lectka培养了一个主要包含本科生的研究小组。这些学生中的大多数人离开了实验室，至少有一个共同著名的出版物，这是一项有价值的成就和证书，以进一步研究科学研究。 Lectka教授的目标是继续吸引少数民族高中生，作为一个学期的科学与工程学（WISE）计划的一部分。研究生和高级本科生参加了由JHU和NSF共同发起的名为SABES的计划。该计划是巴尔的摩市学校与JHU之间的一项由NSF资助的合作，旨在改善STEM学科的教育成果，重点关注社区参与三个社区的资金。与化学部的合成计划的资助，Johns Hopkins University的Thomas Lectka教授的托马斯·洛克斯（Thomas Lectka）的托马斯·霍普克斯大学（Thomas Lectka）的Johns Hopkins University既有新的光学化学方法''，从而使新的光学化学方法不断地介绍了其他光学化学方法。 方法。应用1涉及使用基于羰基的指导组（烯烃，酮和二烯酮）来实现复杂分子的可预测位置选择性。 应用2涉及羧酸衍生物（酰胺，lactams和lactones）作为指导组进行氟化。 再次，可预测的站点选择性是最高目标。 应用3正在解决通过使用相位转移催化，路易斯酸，手性荧光剂以及上述策略的组合，解决了高度映射的现场选择反应的策略。特征是使用可见光发光二极管（LED），廉价的光敏剂和荧光剂，并且功能简单，相互兼容性，轻度条件和广泛的范围也是基本的目标。包括多环天然产物和肽在内的特别复杂的分子的氟化是一个重点，就像在分子中的单个位点实现和理解荧光，并使其具有映选择性。 Lectka教授大量参与了STEM外展计划，例如“科学与工程学女性”（明智）计划和SABE，这是NSF资助的合作，旨在改善巴尔的摩市公立学校的教育成果。 在该研究小组中，本科生（包括许多人为人数不足的小组的成员）进行了大量投资，因此强烈鼓励遵循进入STEM领域的道路。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的审查标准通过评估来获得支持的。

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