Selective Transformations of Common Feedstocks to Functionalized Amines and Heterocycles

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav Selective Transformations of Common Feedstocks to Functionalized Amines and Heterocycles Abstract Nitrogen is the fourth most common element found in FDA-approved drugs, occurring in 88% of the >1000 unique small molecules. The installation of nitrogen into bioactive molecules and pharmaceuticals impacts interactions with biological targets, pharmacokinetics, and pharmacodynamics, as well as myriad physical properties. Given the increased importance of saturation in drug-like molecules, carbon–nitrogen bonds are increasingly stereogenic and thus, methods to incorporate nitrogen should likewise address doing so in stereocontrolled fashion. At the same time, nitrogenated scaffolds are increasingly available from vendors as feedstock chemicals. Amines (in addition to carboxylic acids) are increasingly present in compound libraries given the prominence of amides and the ease of synthesis of this key bond. Herein we propose a multi-pronged approach to synthesize complex structures containing nitrogen substitution from simple precursors, as well as design novel transformations that employ nitrogenous groups as functional handles for further chemical diversification. We seek to address unmet needs in heterocycle synthesis using feedstock chemicals like alkenes and simple alkanes with direct installation of C–C and C–N bonds, obviating post-introduction manipulations. We further aim to transform common amines with either C–H functionalization chemistry or with C–N activation methods for cross-coupling. Taken together, these methods will enable installation and derivatization of nitrogen-containing molecules in a selective fashion while streamlining synthesis to access structures that are highly challenging or impossible to prepare otherwise. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page