New Approaches to Site-Selective Fluorination

点击翻译按钮获取中文摘要

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.