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

Project Information

TRIFLUORO-BUNDLE

Grant agreement ID: 101110967

DOI

10.3030/101110967

Project closed

EC signature date 5 May 2023

Start date 1 September 2023

End date 31 August 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 211 754,88

Coordinated by

UNIVERSITE DE STRASBOURG
France

Periodic Reporting for period 1 - TRIFLUORO-BUNDLE (Utility and Unique Chemistry of Homoallylic Amines with a Difluoromethyl- and Fluoro- Substituted Stereogenic Carbon)

Reporting period: 2023-09-01 to 2025-08-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This project focused on the development of new catalytic strategies for the stereoselective synthesis of easily modifiable organofluorine fragments, as well as the parallel development of reversible catalytic click reactions.
Organofluorine compounds, while rare in nature, play a pivotal role in medicinal chemistry due to their ability to modulate key molecular properties. A major objective was to address the long-standing regarding efficient syntheses of homoallylic amines bearing a polyfluorosubstituted allylic stereogenic carbon center. We successfully established catalytic, diastereo- and enantioselective methods for the synthesis of homoallylic amines bearing polyfluoro-substituted stereogenic centers. The developed strategies allow for precise control over stereochemistry and provide access to complementary diastereomers through distinct catalytic pathways. These protocols enable the efficient generation of valuable fluorinated building blocks, which serve as versatile intermediates for the synthesis of compounds such as polyfluoroamino acids and aza-sugar derivatives, expanding the state of the art in peptide and protein engineering and reinforcing the importance of fluorinated fragments in pharmaceutical and agrochemical innovation.
In parallel, we developed a copper(I)-catalyzed click reaction between allenes and ketones, enabling the formation of robust, yet selectively cleavable linkages under aqueous and physiologically relevant conditions. The resulting organoboron products can undergo controlled cleavage in response to reactive oxygen species (ROS), such as hydrogen peroxide, allowing for targeted and bioresponsive release of molecular payloads. The new reaction platform was also shown to be mutually orthogonal to established copper(I)-catalyzed click reactions, enabling the sequential or simultaneous functionalization of complex molecules. Applications to bioconjugation entailed the synthesis of peptide–drug conjugates, featuring efficient coupling and stimulus-responsive release under biologically relevant conditions.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project delivered significant advances in catalytic methodology and molecular design, contributing new concepts and strategies that extend beyond the current state of the art. Two major outcomes stand out: (1) the development of highly selective catalytic methods for synthesis of homoallylic amines bearing a polyfluorosubstituted allylic stereogenic carbon, and (2) the development of a Cu(I)-catalyzed click reaction generates ROS-triggered cleavable linkages in aqueous media.
The development of highly selective catalytic methods for synthesis of homoallylic amines bearing a polyfluorosubstituted allylic stereogenic carbon: This project delivered key advances in the stereoselective synthesis of polyfluorinated homoallylic amines, molecular architectures of considerable value in medicinal chemistry. The developed strategies enable the precise construction of stereogenic centers bearing multiple fluorine atoms, which are difficult to access by conventional methods. Significantly, the project established a rare case of diastereodivergent synthesis, allowing selective access to different stereoisomers of the same core structure. These structurally distinct analogues offer new opportunities for structure–activity relationship (SAR) exploration and mechanism-of-action (MOA) elucidation, providing valuable chemical space for early-stage drug discovery.
The development of a Cu(I)-catalyzed click reaction generates ROS-triggered cleavable linkages in aqueous media: In parallel, the project introduced a new concept in click chemistry: a reversible carbon–carbon bond-forming reaction that is triggered under biorelevant oxidative conditions. The Cu(I)-catalyzed transformation enables the formation of robust yet cleavable C–C linkages under mild, aqueous conditions, allowing for stimuli-responsive conjugation and release in biological environments. This innovation redefines the boundaries of click chemistry by incorporating chemical reversibility into traditionally static transformations. The method has demonstrated high functional group tolerance and orthogonality to existing bioorthogonal reactions, expanding its potential in complex molecular settings.
Together, these advances provide a powerful toolkit for the design of next-generation therapeutic agents, molecular probes, and dynamic biomaterials. The project highlights the transformative potential of catalysis and molecular design when applied to interdisciplinary challenges at the interface of synthetic chemistry and chemical biology.

Graphical Abstract