Development of a large-scale enantioselective synthesis of a lead compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol core is described. A single isomer of 3,3-disubstituted acrylic acid derivative was prepared via Perkin condensation or Horner-Wadsworth-Emmons olefination, followed by hydrolysis. The acid was converted to a chiral acryloxazolidinone derivative. Hydrogenation of the latter on Pd/C in the presence of MgBr 2 proceeded via a chelation-controlled conformation to yield the desired isomer with high selectivity. Subsequent Evans azidation, hydrogenation, reductive cleavage of the chiral auxiliary, and sulfonylation afforded the target compound as a single isomer in high overall yield.
Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65-84%, while observed regioselectivities were > or =90:10 for 1,8-naphthyridines and > or =84:16 for quinolines.
The preparation of 26f was carried out on a 1.3-mmol scale from the metal acylate 8b23 according to the procedure described above for complex 26a with the reaction parameters indicated in Table l. A single organometallic product was observed by TLC and purified by chromatography on Florisil in the presence of air. The imino complex 26e (Rf 0.22) was obtained in 36% yield (212 mg, 0.47 mmol) as an orange/yellow solid: mp 87-88 °C. Spectral data for 26c:
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