Enantioselective Synthesis of Primary 1‐(Aryl)alkylamines by Nucleophilic 1,2‐Addition of Organolithium Reagents to Hydroxyoxime Ethers and Application to Asymmetric Synthesis of G‐Protein‐Coupled Receptor Ligands.

Abstract

Ligands. -Oximes (I) and (VIII), both derived from methyl (R)-mandelate, are converted into diastereomerically enriched adducts by addition of organolithium compounds. After removal of the chiral auxiliary by N-O bond cleavage the latter give the desired (R)and (S)-amines. Both enantiomers of hydroxyphenyl(ethyl)amine (V), previously used as an efficient chiral auxiliary, are obtained by this method. The synthetic utility of the present method is further demonstrated by the synthesis of calcium receptor agonist NPS R-568 (VIc) and its thio analogue (VIh), and by transformation of vinyl derivative (R)-(IVg) into NK-1 receptor antagonists CP-99,994 and CP-122,721 (VII). -(ATOBE, M.; YAMAZAKI, N.; KIBAYASHI*, C.; J. Org. Chem. 69 (2004) 17, 5595-5607; Sch. Pharm., Univ. Pharm. Life Sci., Hachioji, Tokyo 192, Japan; Eng.) -Klein 51-068