Thierry Lequeux

Efficient introduction of a difluorophosphonylated allyl or propyl thioether onto the 2'-position of adenosine is described. Following the preparation of phosphoramidites derived from these compounds, oligonucleotides incorporating these new chemical modifications were prepared successfully using a 12-mer model sequence. UV-melting experiments revealed a significant decrease in the thermal stability of modified RNA/RNA duplexes. In contrast, enzymatic degradation studies showed that the difluoromethylphosphonate group slows down enzymatic degradation while simultaneously increasing lipophilicity.

The synthesis of fluorinated acyclonucleos(t)ides and their prodrugs is reported based on the selective preparation of tetrasubstituted fluoroalkenes as key intermediates. Two methods were developed involving an early- or a late-stage introduction of the nucleic base depending on the target compound. The preparation of known drugs and analogues was reported.

The synthesis of a new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker, and/or the amino-acid N-terminal moiety in order to increase in vivo stability and cell permeability. These new compounds were evaluated in vitro as DltA inhibitors and also in vivo as adjuvant antibiotics to re-sensitize methicillin-resistant Staphylococcus aureus. Indeed, we showed that seven nucleosides containing either a fluorine atom, an azido group, a difluorophosphonylated allylic ether moiety onto the 2′-position, or a sulfamate and a triazole as the sulfamate linker had moderate to excellent IC₅₀ values. Among all these new DltA inhibitors, two molecules functionalized by the fluorinated ether or the sulfamide linker were able to efficiently re-sensitize MRSA to imipenem. Quantification of D-alanyl esters confirmed that these two compounds reduced the level of bacterial cell wall D-alanyl residues by 50% and 80%.

The synthesis of new acyclic and cyclic series of D-Ala-AMP analogues was reported. Chemical modifications were introduced on the carbohydrate, the sulfamate linker and/or the amino-acid N-terminal moiety in order to increase in vivo stability and cell permeability. These new compounds were evaluated in vitro as DltA inhibitors and also in vivo as adjuvant antibiotics to re-sensitize methicillin resistant Staphylococcus aureus. Indeed, we showed that compounds 8, 9, 18, 27, 28, 35 and 36, containing modifications onto the carbohydrate or the linker, had moderate to excellent IC50 values. We also showed that 18 and 27 were able to efficiently re-sensitize MRSA to imipenem. Quantification of D-alanyl esters confirmed that these two compounds reduced the level of bacterial cell wall D-alanyl residues by 50% and 80%.

The ring-opening reaction of fluorinated oxetanes by halides, including alkylidene oxetanes and spirocyclic oxetanes, was highly stereoselective and directed by the presence of a fluorine atom. This reaction allowed a stereoselective preparation of tetrasubstituted alkenes and substituted pyrrolidines containing all-carbon quaternary centers. Theoretical calculations were performed to shed light on experimentally observed regioselectivity in the opening of oxetane derivatives. Transition state calculations were carried out to compare the energy of transition states responsible for forming different diastereoisomers. These calculations were performed using several DFT functionals and benchmarked to DLPNO-CCSD(T)/def2-TZVP calculations. Intrinsic reaction coordinated (IRC) calculations were run to confirm if the found transition states connect reactants and products. The IRC paths were then decomposed into the electrostatic, steric hyperconjugative contributions to reaction barriers by using the natural bond orbital (NBO) analysis. The destabilizing F delta-Br- electrostatic interaction directs the reaction pathway.

Fluoroalkenes have been known for decades, but their preparation is still a hot topic. Indeed, the olefination reactions of carbonyl compounds with fluorinated derivatives are not trivial. For that reason, new tools have been developed to efficiently access tri- and tetrasubstituted alkenes. We report our contribution in this field and their interest will be illustrated by the preparation of dipeptide isosteres and acyclonucleoside analogues.

Scope and limitations of the group transfer radical reaction of diisopropyl iododifluoromethylphosphonate onto carbohydrates and nucleosides are described. This key step allowed us to explore the synthesis of new fluorinated nucleoside analogues containing a difluorophosphonylated allylic ether moiety onto the 2'-position, in purine and pyrimidine series (B = A, C, G, T, U). Indeed, two unprecedented chemical approaches involving a late introduction of either the nucleobase or the fluorinated moiety are discussed.

The synthesis of undescribed β‐aminodifluoroethylsulfinates and their uses in the hydroaminodifluoroalkylation of alkenes is reported. This reaction is performed in the presence of a photocatalyst (4CzIPN, Ru complexes) and enables the direct incorporation of a β‐difluoroamine moiety into vinylic aryls, unactivated alkenes, and electron‐rich, or ‐deficient alkenes. The mechanism was studied, and the formation of a gem‐difluoromethyl radical was observed after the selective oxidation of the sulfinate function.

The photocatalyzed dearomative reaction between various electron‐deficient aromatic compounds and a non‐stabilized azomethine ylide is successfully performed in a flow system. Whereas the use of supported eosin as organic photocatalyst exhibits limited efficiency, turning to the soluble Rose Bengal allows to transform a broad range of substrates from hetarenes (indole, benzofuran, quinoline, pyridine) to naphthalenes and benzenes. This photocatalyzed (3+2) dearomative cycloaddition under green light irradiation provides a simple and efficient access to tridimensional pyrrolidino scaffolds with a tetrasubstituted carbon center at ring junction and can be performed in the friendly ethyl acetate. Computational studies support the mechanism involving azomethine ylide as reactive species toward the electron‐poor arene.

Tri‐ and tetra‐substituted alkenes, including fluoroalkenes, were prepared by a selective ring‐opening reaction of functionalized oxetanes. The introduction of adenine nucleic base allows the synthesis of alkenyl and fluoroalkenyl derivatives that were evaluated towards DltA enzyme as potential nucleoside mimics.