A highly stereocontrolled synthesis of (S-(-)-3-(4-tert-butyl)phenyl-1-N-(cis-2,6-dimethyl)morpholinyl-2-methylpropane via assymetric mannich reaction

Abstract

By employing cis-2,6-dimethylmorpholinemethylene immonium tetrachloroaluminate (5) enamines 9 and 10, prepared from 4-tert-butylpropiophenone and propiophenone with (R)-(-)-2-(methoxymethyl)pyrrolidine (8), were converted to chiral Mannich bases 11,12 with nearly 100% ee; optical purity of these β-amino ketones drops significantly during isolation. Two-step reduction of the keto group in 11,12 afforded (S)-(-)-3-(4-tert-Butyl)phenyl-1-N-(cis-2,6-dimethyl)morpholinyl-2-methylpropane (1), (S)-enantiomer of racemic systemic fungicide, generic name fenpropimorph, and its congener 13 with 95.1% and 90.7% ee, respectively. A mechanistic model for asymmetric induction in the diastereoselective step is proposed.