Chiral 4-Phenyl-2-trifluoromethyloxazolidine: A High-Performance Chiral Auxiliary for the Alkylation of Amides

摘要

Chiral-auxiliary-based alkylation at the -position of amides remains the strategy of choice for the preparation of various building blocks useful for the synthesis of bioactive compounds. Oxazolidinones[1] and related heterocyclic structures,[2] sultames,[3] and amino alcohols, such as pseudoephedrine,[4] count among the most efficient chiral auxiliaries reported. The use of oxazolidines as chiral auxiliaries for the diastereoselective alkylation of amide enolates has rarely been reported.[5] This is probably due to the harsh reaction conditions required for the removal of the aminoacetal functional group and its low stability. Although the introduction of fluorine atoms into molecules dramatically perturbs their physical and chemical properties,[6] little is known about the use of fluorine-containing chiral auxiliaries in asymmetric synthesis.[7] Chiral 2-trifluoromethyloxazolidines were first reported by Mikami and co-workers[8] and have recently found several applications as synthons in the stereoselective synthesis of chiral trifluoromethylated amines and amino acids.[9] We now report their use as chiral auxiliaries for highly diastereoselective alkylation reactions of amide enolates. The introduction of the trifluoromethyl group in the 2-position of the oxazolidine ring is intended to increase its stability to hydrolysis and to enable the chiral auxiliary to be recovered. Unique effects of the fluorinated group on the diastereoselectivity are also expected.