TRIFLUORO-BUNDLE · Utility and Unique Chemistry of Homoallylic Amines with a Difluoromethyl- and Fluoro- Substituted Stereogenic Carbon

Utility and Unique Chemistry of Homoallylic Amines with a Difluoromethyl- and Fluoro- Substituted Stereogenic Carbon

The strategic context of this project lies at the intersection of synthesis method development, molecular design, and the evolving needs in biological chemistry, pharmaceutical, and agrochemical. Fluorinated compounds remain rare in nature, yet they constitute essential components in more than 20% of marketed drugs and an increasing number of agrochemical products due to their ability to enhance bioavailability, metabolic stability, and membrane permeability. However, efficient and stereoselective methods for constructing modifiable fluorinated motifs, particularly polyfluorinated allyl amines, are underdeveloped, limiting general access to these key compounds which are needed for the development of the next generation of bioactive molecules. The aim of this project was to address the foregoing shortcoming in the state-of-the-art by developing a catalytic method for the enantioselective synthesis of homoallylic amines bearing a polyfluoro-substituted allylic stereogenic center. Such entities could then serve as key intermediates toward the synthesis of fluorinated amino acids and aza-sugar derivatives. These structures are increasingly relevant in peptide and protein engineering as well as in the development of therapeutics targeting challenging biological pathways. Two complementary catalytic strategies were established, enabling the stereocontrolled assembly of valuable fluorinated scaffolds from readily available precursors. These advances lay the groundwork for new synthetic entry points into fluorinated analogues of biologically relevant molecules. In parallel, the project tackled a broader conceptual challenge in molecular construction: the need for click reactions that not only form robust and selective linkages under mild, aqueous conditions, but, equally important, can be reversibly cleaved triggered by key biological stimuli. The development of the Cu(I)-catalyzed allene–ketone addition (CuAKA) reaction demonstrated that common ketones can be used as effective, bioorthogonal click partners. The resulting linkages are cleavable upon exposure to physiologically relevant levels of reactive oxygen species (e.g., H2O2), enabling controlled release of drug payloads. This chemistry expands the scope of bioconjugation techniques by offering both modularity and reversibility, critical for targeted drug delivery systems and responsive therapeutic platforms. The orthogonality of CuAKA to other Cu-based click methods (CuAAC and CuPDF) also enhances its utility in multi-functional systems where precise chemical control is essential. Overall, the fellowship research contributes a suite of unprecedented catalytic strategies and design principles with the potential for broad impact in synthetic chemistry, drug discovery, and biomaterials. These outcomes directly address key challenges identified in EU and global research priorities, including the development of enabling technologies for health and sustainability.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз