New Approaches to Site-Selective Fluorination

在药品市场上，近四分之一的顶级药物含有氟；因此，将氟安装在分子中已成为化学家面临的一个重要问题。事实上，在药物化学中，“氟化筛选”已经司空见惯。在这种方法中，分子在每个可访问的位置被有条不紊地氟化，以提供新的候选对象进行评估。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，P.I.约翰斯·霍普金斯大学的托马斯·莱特卡教授正在开发一种方法，以选择性的方式安装氟，这将允许新的和理想的大氟化生物活性分子的通道。简单的反应条件、安全性和易用性也是重要的目标。重点介绍了包括天然产物和多肽在内的特别复杂分子的氟化。化学家们对这些类型的分子越来越感兴趣。就更广泛的影响而言，PRF。莱特卡培养了一个研究小组，成员主要是本科生。这些学生中的大多数离开实验室时都至少带着一份共同撰写的出版物，作为进一步研究科学的有价值的成就和证书。莱特卡教授的目标是在一个学期内继续吸引少数族裔高中生参加女性科学与工程(WISE)项目。研究生和高级本科生参加由JHU和NSF共同发起的名为Sabes的项目。这个项目是由NSF资助的巴尔的摩城市学校和JHU之间的合作，旨在改善STEM学科的教育结果，重点是三个社区的社区参与。在化学系合成项目的资助下，约翰霍普金斯大学的Thomas Lectka教授正在开发专注于现场选择性氟化的新的光化学方法，以生产化学和药物方面的有趣产品，这些产品是其他方法很难获得的。应用1涉及使用基于羰基的导向基团(酮、酮和二烯酮)来实现复杂分子上可预测的位置选择性。应用2涉及作为氟化的直接基团的羧酸衍生物(酰胺、内酰胺和内酯)。同样，可预测的选址是最重要的目标。应用3正在解决通过使用相转移催化、Lewis酸、手性氟化剂以及上述策略的组合来使位置选择性反应具有高度非对映选择性的策略。使用可见光发光二极管(LED)、廉价的光敏剂和氟化剂是其特点，操作简单、相互兼容、条件温和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多肽的氟化是一个重点，在分子中的单个位置实现和理解氟化并使其成为非对映选择性是一个重点。莱特卡教授积极参与STEM外展计划，如“女性参与科学与工程”(WISE)计划和Sabes，这是一个由NSF资助的合作项目，旨在改善巴尔的摩市公立学校的教育结果。在这个研究小组中，本科生(包括许多代表不足的群体的成员)被投入大量资金，因此高度鼓励他们走上STEM领域的道路。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和更广泛的影响审查标准进行评估，被认为值得支持。

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.