Asymmetric Synthesis of β-Substituted γ-Lactams Employing the SAMP-/RAMP-Hydrazone Methodology. Application to the Synthesis of (R)-(-)-Baclofen

A short and efficient asymmetric synthesis of β-substituted γ-lactams is described.Key steps are the α-alkylation of aldehyde SAMP-hydrazones with alkyl bromoacetates, their MMPP mediated conversion to the corresponding nitriles and a reductive cyclization with Raney Ni or Ni boride to the title pyrrolidin-2-ones.The β-substituted γ-lactams are obtained in three steps, good overall yields (27-78%) and excellent enantiomeric excesses (ee = 93-99%).The applicability of this procedure for the asymmetric synthesis of GABAs (γ-aminobutyric acids) is demonstrated for (R)-(-)-baclofen hydrochloride, which is obtained in 4 steps, 55% yield and 94% ee.