Tetrafluoroethyl and tetrafluoroethylene group transfer
Starting from dibromotetrafluoroethane we have synthesized a variety of nucleophilic and radical sulfur-containing compounds, which are now under investigation as reagents for tetrafluoroethyl and tetrafluoroethylene group transfer (European Journal of Organic Chemistry 4528-4531, 2011; Synlett 1187-1190, 2012; Journal of Fluorine Chemistry 156: 307-313, 2013; Journal of Fluorine Chemistry 171: 162-168, 2015; Chemistry - A European Journal 417-424, 2016).
Magnesiation of tetrafluoroethyl-containing bromides with Turbo Grignard reagents led to the formation of organomagnesium compounds, which were stable at low temperature and reacted with various electrophiles to afford novel functionalized tetrafluoroethylene-containing products (Organic Letters 18: 5844-5847, 2016).
In collaboration with the group of Prof. Togni (ETH, Zurich) a series of new hypervalent iodine reagents was prepared and used for electrophilic CF2CF2 transfer (Chemistry - A European Journal 22: 417-424, 2016).
The exceptionally good reactivity and selectivity of these hypervalent iodine reagents toward thiols prompted us to investigate conjugation to biological thiols. A secondary amine platform reagent was designed, converted to amide, sulfonamide or termiary amine and in collaboration with Prof. Hilvert (ETH Zurich) studied for bioconjugation of a retroaldolase enzyme (Chemistry - A European Journal 23: 6490-6494, 2017). Our reagents have several advantages over existing commercial thiol conjugation reagents: modular synthesis with a variety of functional groups attached in the last step (fluorophore, biotin, PEG, reactive handle), exceptional selectivity for thiols, fast reaction rates and high stability of the conjugate.
Cyclic hypervalent iodine reagents used for fluoroalkylation of thiols can be used also for fluoroalkylation of tryptophan and other aromatic amino acids. This was achieved by adding a suitable water-soluble and biocompatible reductant (sodium ascorbate) which induces the formation of fluoroalkyl radicals. The process was demonstrated on numerous indoles, peptides and proteins where targeting Trp was very selective (Chemistry – A European Journal 25: 15779).
Interestingly, without the reductant in the presence of a blue light the iodine reagents are decomposed to form fluoroalkyl radicals as well. The method has been applied for derivatization of Trp-containing biomolecules (ChemPhotoChem: in press).
We collaborated with Petr Novák from Charles University and BIOCEV on the development of fast fluoroalkylation of proteins using hypervalent iodine compounds and a biocompatible reductant. These modification uncovered the structure and dynamics of protein complexes and protein-protein interactions (Journal of the American Chemical Society 143: 20670-20679, 2021).