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Practical Enantioselective Synthesis of a 3-Aryl-3-trifluoromethyl-2-aminopropanol Derivative

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journal contribution
posted on 20.11.2009, 00:00 authored by Asaf Alimardanov, Antonia Nikitenko, Terrence J. Connolly, Gregg Feigelson, Anita W. Chan, Zhixian Ding, Mousumi Ghosh, Xinxu Shi, Jianxin Ren, Eric Hansen, Roger Farr, Michael MacEwan, Sam Tadayon, Dane M. Springer, Anthony F. Kreft, Douglas M. Ho, John R. Potoski
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 MgBr2 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.