Catalyst Project: New Hydrazine Reagents for Late-Stage Diversification of Bioactive Molecules

Catalyst Projects provide support for Historically Black Colleges and Universities (HBCU) to work towards establishing research capacity of faculty to strengthen science, technology, engineering, and mathematics (STEM) undergraduate education and research. It is expected that the award will further the faculty member's research capability, improve research and teaching at the institution, and involve undergraduate students in research experiences. This award to Lincoln University (MO) supports faculty and undergraduate research experiences in the development of cyclic-bis(silyl)hydrazines, a novel class of hydrazine reagents. Specifically, the proposal seeks to create the first strong metal-base free Wolff-Kishner type gem-difluorination of carbonyl carbons (C=O) under neutral conditions, result in synthetically made bioactive molecules. The overarching goal of the proposal is to develop a new metal-base free late-stage gem-difluorination technique for converting the carbonyl carbon (C=O) of aldehydes and ketones into CF2 group, resulting in a new class of hydrazine reagents. This project has been divided into five specific aims: (1) to develop synthetic and purification protocols for the proposed cyclic-bis(silyl)hydrazine reagents, (2) to study the tautomeric equilibrium of the new cyclic-bis(silyl)hydrazine reagents in different organic solvents and assess their hydrolytic stability, (3) to develop a general method for synthesis of hydrazones using cyclic-bis(silyl)hydrazine reagents, (4) use the cyclic-bis(silyl)hydrazones to develop a new gem-difluorination methodology of carbonyl carbon of aldehydes and ketones, and (5) validate the utility of the proposed fluorination technique by performing the gem-difluorination of a bioactive complex molecule, hecogenin acetate. Basic synthetic chemistry principles and techniques will be used to synthesize the novel reagents. These compounds will be purified using flash column chromatography and characterized by 1H, 19F, 13C-NMR, and HRMS techniques. Progress of the reaction will be monitored by Thin Layer Chromatography (TLC) and 1H, 19F NMR. Successful completion of the proposed research will provide new cyclic-bis(silyl)hydrazine reagents for late-stage gem-difluorination of carbonyl carbon (C=O) of ketones and aldehydes without using any strong metal-base. 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.