Two Complementary Approaches to Site-Selective HAT and ET Reactions

With support from the Chemical Synthesis Program in the Division of Chemistry, Professor Thomas Lectka of Johns Hopkins University will study new ways to selectively modify one specific carbon-hydrogen or carbon-carbon bond in a large complex molecular scaffold. In recent years, organic chemists have sought to synthesize new derivatives of complex natural products of medicinal value through reactions at one particular site among many possible sites in a molecule. There are major challenges for site selectivity in such important late stage modifications with the potential to afford derivatives of practical value to chemistry, biology, and medicine. The Lectka research team will approach such site selectivity through two different strategies. The first strategy employs hydrogen bonds to guide reactivity in well-structured substrates, leading to site-selective functionalization reactions. In the second strategy, undesirable sites in a complex substrate are deactivated through the binding of a metal ion to the fragment that needs to be neutralized. The proposed research activities will provide a strong training platform for the professional development of graduate students and research experiences for undergraduate students. Professor Lectka and his research team will partner with the JHU Women in Science and Engineering (WISE) program, the Pioneer Program for high school students, and the Goucher Prison Education Partnership Program in outreach to the broader local and national communities. Under this award, the Lectka research team will involve directing intermolecular hydrogen atom transfer (HAT) and, in some cases, electron transfer (ET) to specific sites within a variety of complex molecules through two fundamental and complementary strategies. The first strategy will employ hydrogen bonds to guide HAT and ET in well-structured substrates through functional group direction, leading to site-selective functionalization reactions to form new carbon-fluorine and carbon-carbon bonds diastereoselectively and potentially enantioselectively. In the second strategy, undesirable sites in a complex substrate will be deactivated through the binding of a metal ion to the fragment that needs to be neutralized. In the case of an electrophilic reaction, positive charge repulsion, induced steric effects, and electron withdrawal will provide the necessary deactivation and proof of principle. This new approach contrasts with the traditional approach to site selectivity involving the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site. Site selective functionalization in complex molecular settings is a current great challenge in chemistry motivated by the desire to be able to study and modify natural products and practical pharmaceutical targets without having to individually prepare each analogue from basic building blocks. A new, complementary approach to siteselectivity would thus be of great import to fields such as medical and biological chemistry. 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.