The identification and development of a catalyst for the enantioselective nucleophilic addition of a trifluoromethyl anion to a ketone is described. An easily prepared cinchonine-derived catalyst was used in amounts as low as 4 mol% to afford enantiomeric excess as high as 92%.
CJ-17,493 (4) is a chiral NK-1 receptor antagonist. It was first prepared through a diastereoselective crystallization, then through chiral chromatography of a key intermediate, and ultimately via asymmetric synthesis. Multiple routes for the preparation of a key isochroman were demonstrated, and conditions for improved regioselectivity of a Friedel-Crafts acylation were identified. Cesium fluoride was found to be an acceptable initiator for the generation of a nucleophilic trifluoromethyl anion from CF 3 TMS. A cinchonine-derived catalyst was identified for the enantioselective addition of the trifluoromethyl group to the ketone, and it was found that the product of the addition would be converted directly to the isochroman by treatment with t-BuOK. A Duff reaction was used for the formylation, and the resulting aldehyde was coupled to amine 5 to afford CJ-17,493 (4).
Two families of biarylphosphine ligands were prepared for use in the Pd-catalyzed amination reaction. The first series investigated was derived from N-phenylpyrroles, and the second, was derived from N-phenylpyrazoles. While the pyrrole ligands were not as general in substrate scope, one of the readily prepared pyrazole ligands (R = t-Bu) was found to have a fairly broad substrate scope.
Amines
Amines Q 0120Alternative Biarylphosphines for Use in the Palladium-Catalyzed Amination of Aryl Halides. -Two related families of phosphine ligands (I) and (II) are prepared. None of them has the general scope, but (IIb) appears to be the most effective agent. -(SINGER*, R. A.; CARON, S.; MCDERMOTT, R. E.; ARPIN, P.; DO, N. M.; Synthesis 2003, 11, Special Issue, 1727-1731; Chem. Res. Dev., Pfizer Inc., Groton, CT 06340, USA; Eng.) -C. Herrmann 50-086
Enantioselective syntheses
Enantioselective syntheses O 0031Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes. -The addition reaction is optimized by studying the influence of the alcohol protection group, the structure of the catalyst and the reaction condition. The best results concerning conversion (97%) and enantioselectivity (92%) are obtained with cinchonine derivatives (Ia) and (Ib). -(CARON*, S.; DO, N. M.; ARPIN, P.; LARIVEE, A.; Synthesis 2003, 11, Special Issue, 1693-1698; Chem. Res. Dev., Pfizer Inc., Groton, CT 06340, USA; Eng.) -C. Herrmann 50-031
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