CBL Chemical Biology Lab

Asymmetric Synthesis of Fluorinated Compounds

Since September 2002, our group is focused in the development of stereoselective methods for the preparation of chiral organofluorinated compounds. The introduction of fluorinated group into molecules modifies their stereoelectronic properties, and consequently their physical and biological properties. Thus, organofluorinated compounds have received a great attention this last years in the field of medecinal chemistry as well as in materials. In this context, we have developed several efficient and stereoselective routes for the preparation of trifluoromethylated amines, aminoacids, aminoalcohols or diamines. Our strategy is based on the use of chiral fluorinated oxazolidines FOX. The use of Strecker-type reaction allows the introduction of nitrile group and gives a direct access to the corresponding alfa-Tfm-aminoacids, alfa-Tfm-aminoalcohols or alfa-Tfm-diamines. Manich-type addition affords to beta-Tfm-beta-aminoacids, beta-Tfm-beta-aminoketones or gama-Tfm-gama-aminoalcohols derivatives. Reformatsky reagent gives alfa-Tfm-beta-lactam, precursor of beta-Tfm-beta-aminoacids. Finally, allylation or alkynylation reactions of oxazolidines afford to the homoallylic alfa-Tfm-amine and propargylic alfa-Tfm-amine derivatives. The stereoselectivity for these reactions are from moderate to good but in any cases, the diastereomers are easily separated by flash chromatography thanks to the effect of the trifluoromethyl group on molecular conformation. Our group has also developed an original method for the preparation of alfa-Tfm-amines. Addition of organometallic reagents (Grignard or organolithium reagents) on hydrazone intermediate derived from fluoral are highly stereoselectives.

Highly Diastereoselective Synthesis of Enantiopure β-Trifluoromethyl β-Amino Alcohols from Chiral Trifluoromethyl Oxazolidines (Fox), Simon, J.; Chelain, E.; Brigaud, T. Org. Lett., 2012, 14 (2), 604–607.

Straightforward synthesis of enantiopure (R)- and (S)-trifluoroalaninol, Pytkowicz, J. ; Stephany, O. ; Marinkovic, S. ; Inagaki, S. ; Brigaud, T. Org. Biomol. Chem. 2010, 8, 4540-4542.

Concise synthesis of enantiopure α-trifluoromethyl alanines, diamines and amino alcohols via the Strecker-type reaction, Huguenot, F. ; Brigaud, T. J. Org. Chem. 2006, 71, 7075-7078.

 Fries, S.; Pytkowicz, J.; Brigaud, T. Tetrahedron Lett. 2005, 45, 4761-4764.

Lewis acid activation of chiral 2-trifluoromethyl-1,3-oxazolidines. Application to the stereoselective synthesis of trifluoromethylated amines, α- and β-amino acids, Lebouvier, N. ; Laroche, C. ; Huguenot, F. ; Brigaud, T. Tetrahedron Lett. 2002, 43, 2827-2830.

In collaboration with Portella’s group (University of Reims-Champagne Ardenne, UMR 6519), the nucleophile and electrophile reactivity of difluoroenoxysilanes have been studied for the preparation of various chiral difluorinated compounds. Difluoroenoxysilanes obtained from acylsilanes and CF3SiMe3 present a nucleophile behavior. Reactions with chiral imines or oxazolidines give chiral difluoro-beta-aminoketones.

Synthesis of trifluoromethyl cyclohexyl, cyclohexenyl and aryl compounds via stepwise Robinson annulation, Massicot, F.; Iriarte, A. M.; Brigaud, T.; Lebrun, A.; Portella, C. Org. Biomol. Chem. 2011, 2, 600-603.

Jonet, S. ; Cherouvrier, F. ; Brigaud, T. ; Portella, C. Eur. J. Org. Chem. 2005, 20, 4304-4312.

Difluoroenoxysilanes present also an electrophilic behavior. Condensation with chiral aminoalcohols affords the corresponding chiral oxazolidines, which are valuable materials for the preparation of difluoroamines and difluoroaminoacids in enantiopure form.

Huguenot, F. ; Billac, A. ; Brigaud, T. ; Portella, C. J. Org. Chem. 2008, 73, 2564-2569.