Vinylfluorides by superacid mediated fluorination of heteroatom substituted alkynes – VINFLUSUP

In this collaborative project, joint efforts in copper catalysis, superacid chemistry as well as a combined experimental and theoretical approaches were used to develop general and efficient transformations from heteroatom-substituted alkynes in superacid. The complementary and synergistic nature of the collaboration provided strong bases for achieving the goal of the proposed project: The synthesis of new heteroatom-substituted fluoroolefins and their evaluation as bioisosters.

The ability to access to new fluoroenamides compounds, through superacid catalyzed hydrofluorination of ynamides has been proved. Theoretical calculations at the MP2 and B3LYP levels of theory showed that the resulting fluoroenamides exhibit geometrical and electronic properties that partially mirror those of ureas, therefore demonstrating that the hydrofluorination of ynamides provides a general, straightforward and user-friendly approach to analogues of ureido isosters, potent building blocks for biological studies and medicinal chemistry. In addition, the mechanistic studies allowed to perfectly apprehend the reactivity of ynamides under those conditions, work which allowed to discover a new reaction. The highly efficient keteniminium-initiated cationic polycyclization affords a straightforward entry to nitrogen heterocycles possessing up to three contiguous stereocenters and seven fused cycles that can be obtained in a single operation from readily available ynamides. The convenient access to the core of alkaloid haouamine A based on this method underscores its potential utility in medicinal chemistry and natural product synthesis.

In the context of a young researcher project, this project aimed at developing an innovative research, with no equivalent in France and scarcely developed in the world. Following a precise timetable, a large set of objectives have been reached, allowing the synthesis of versatile new fluoroolefins derivatives, which can be considered as ureido rigid bioisosters. These data have been spotlighted in high impact factor journals on front page cover (Chem. Commun, J. Am. Chem. Soc.). It makes no doubt that this new class of compounds will find applications in scientific domains going from catalysis to medicinal chemistry.

The obtained results of VINFLUSUP project led to the publication of articles in high impact factor scientific journals (8 articles) and to invited conferences in national and international symposiums (35 conferences). Two of the publications were highlighted as front cover of the journals and spotlighted by the editor of the journal. It has also to be noted that the PhD student recruited on this project won the communication prize in a national meeting.

Because of its intriguing properties, fluorine is a crucial element in medicinal chemistry. The strategic use of fluorine substitution in drug design has indeed culminated in 25 percent of drugs in the pharmaceutical pipeline containing at least one fluorine atom and 50% of all agrochemicals. Among all fluorine substitution studied and used in pharmaceutical industry, the substitution of amide with fluoroolefins clearly is one of the most popular strategies and has considerable potential. They have been suggested as being superior isosteric replacement for carboxamide groups and are therefore of considerable interest in the synthesis of peptidomimetics and/or enzyme inhibitors. Further developments in the use of fluoroalkenes will therefore strongly rely both on the design of new and selective synthetic methods for their preparation and the introduction of new building blocks that would broaden the variety of fluoroalkenes available and their diversity. In this perspective, heteroatom-substituted fluoroolefins, which have only been scarcely reported in the literature and that can hardly be prepared, are an especially appealing class of molecules. They could act as bioisosters of ureas, carbamates and thiocarbamates, lead pharmacophores that could be used for the design of novel enzyme inhibitors. Despite the potent applications that could offer the bioisosteric substitution of these functions by fluoroolefins analogues, this strategy has however never been explored to date, which is most certainly due to the lack of methods for the preparation of a-heteroatomic fluorovinyl compounds. A simple solution to this problem would rely on the hydrofluorination of heteroatom-subtituted alkynes, a reaction that has surprisingly never been studied.

In this context, the main goal of the proposed project is to develop a novel general method to access to a-fluoroenamines, a-fluoroenolether and a-fluorothioenolether by applying original superacid chemistry to heteroatom substituted alkynes, to show that these novel functionalized fluoroalkenes could be respectively used as fluorinated bioisosters of ureas, carbamates and thiocarbamates.

In this collaborative project, joint efforts in catalysis for the development of new routes to heteroatom-substituted alkynes and superacid chemistry for the hydrofluorination process as well as a combined experimental and theoretical approach will be utilized to develop general and effective transformations from heteroatom-substituted alkynes in superacid HF/SbF5. The complementary and synergistic nature of the collaboration provides strong bases for achieving the goal of the proposed project.