Asymmetric Catalysis and Selective C-F Bond Functionalization with Organofluorines

项目摘要

PROJECT ABSTRACT The ever-increasing demand for synthetic tools that expand currently available chemical space and provide efficient access to new biologically active compounds has shifted significant attention toward the development of methods that produce chemically versatile multifunctional fluorinated chiral compounds or accomplish carbon-fluorine bond functionalization in new ways that remove long-standing boundaries of traditional chemical synthesis. Despite considerable progress, in particular with hydrodefluorinations, these tasks remain quite difficult because the profound electron-withdrawing and stereoelectronic effects of fluorine often interfere with established synthetic protocols and dramatically alter reaction outcomes compared to nonfluorinated analogs. Given the abundance and diversity of readily available fluorinated building blocks that await chemical modification, the introduction of methodologies that overcome these challenges are expected to set the stage for new synthetic tools and possibilities that streamline or enable the production of current and future drugs. The proposed research aims to introduce carbon-fluorine bond activation chemistry and asymmetric methods that combine exceptional reaction control, scope and functional group tolerance. The C-F bond, typically considered chemically inert, will become a strategically useful entity that can be selectively activated under mild reaction conditions which will open the door to a variety of unprecedented applications including late-stage functionalization and stereoselective carbon-carbon bond formation. In addition, (organo)catalytic asymmetric methods that efficiently produce fluorinated structures exhibiting one or two elements of chirality, a wide range of functional groups, and pharmaceutically relevant motifs will be introduced. These efforts will afford a diverse pool of synthetically versatile structures with broad utility and respond to the rapidly increasing demand for high-yielding stereodivergent and atroposelective procedures among the synthetic and medicinal chemistry communities. While emphasis lies on the introduction of new synthetic methodologies and asymmetric catalysis development, the mechanistic underpinnings will be fully explored to guide optimization efforts and to stimulate similar efforts and discoveries in other research groups. The general feasibility and the corresponding prospects are supported by ample proof-of-concept results that show how organofluorines can be prepared and utilized in currently not possible ways. Finally, the suitability of the proposed transformations for the synthesis of biologically active compounds will be demonstrated.