Our Team develops methodologies involving chiral auxiliaries derived from trifluoromethylated oxazolidines (FOX) towards amide enolates alkylation, hydroxylation or fluorination. The excellent diastereoselectivities obtained and the possibility to use sterically hindered substrates allow a direct and efficient access to enantiomerically pure α-substituted acids, aldehydes and β-substituted alcohols. Moreover the chiral auxiliary is recovered in good yield at the end of the synthesis. A DFT study correlated with experimental data revealed a critical Fluorine-Metal interaction that rigidifies the transition state and orientates the electrophile approach. A competing π-metal interaction ends up to the formation of the same diastereomer thanks to the pseudo-C2 symmetry of the auxiliary.
Crystallization-Induced Dynamic Resolution of Fox Chiral Auxiliary and Application to the Diastereoselective Electrophilic Fluorination of Amide Enolates. Lubin, H.; Dupuis, C.; Pytkowicz, J.; Brigaud, T. J. Org. Chem., 2013, 78 (7), 3487-3492.
Highly Diastereoselective alfa-Hydroxylation of Fox Chiral Auxiliary-Based Amide Enolates with Molecular Oxygen, Lubin, H. ; Tessier, A. ; Chaume, G. ; Pytkowicz, J. ; Brigaud, T. Org. Lett. 2010, 12, 1496-1499.
Chiral 2-trifluoromethyl-4-phenyloxazolidine : A novel highly performing chiral auxiliary for amides alkylation, Tessier, A. ; Pytkowicz, J. ; Brigaud, T. Angew. Chem. Int. Ed. Engl. 2006, 45, 3677-3681.
Highly diastereoselective synthetic route to enantiopure β2-amino acids and γ-amino alcohols using a fluorinated oxazolidine (Fox) as chiral auxiliary, Tessier, A. ; Lahmar, N. ; Pytkowicz, J. ; Brigaud, T. J. Org. Chem. 2008, 73, 3970-3973.
Fluorine••• and π•••Alcali Metal Interactions control in the Stereoselective Amide Enolates Alkylation using Fluorinated Oxazolidines (Fox) as Chiral Auxiliary : An Experimental and Theoretical Study, Sini, G. ; Tessier, A. ; Pytkowicz, J. ; Brigaud, T. Chem. Eur. J. 2008, 14, 3363-3370.