SYNTHESIS OF THE INDIVIDUAL ENANTIOMERS OF THE BENZOQUINOLINONE HUMAN TYPE-1 STEROID 5-ALPHA-REDUCTASE INHIBITORS LY191704 AND LY266111

The first syntheses of the individual enantiomers of the benzoquinolinone class of selective inhibitors of human Type 1 steroid 5-alpha-reductase are described. For benzoquinolinones lacking an angular substituent, the approach relies upon an enamine acryloyl chloride cyclization followed by non-stereoselective reduction and diastereomer separation. Absolute configuration was established by single crystal x-ray diffraction analysis. The angularly methylated benzoquinolinones are prepared in an enantiospecific (deracemizing) fashion from 1-methyl-6-chloro-2-tetralone in 5 steps, employing a ''formal 3 + 3 aza-annulation'' sequence, with (R) or (S) alpha-phenethylamine as the source of chirality.