New asymmetric synthesis of (−)-esermethole

A new synthesis of (-)-esermethole, based on the asymmetric alkylation at C(3) of racemic 1,3-dimethyl-5-methoxyoxindole (3), is described. The chloroacetyl derivatives of (-)-menthol and (S)-N-methyl-(1-phenylethyl) amine were chosen as chiral alkylating agents and used under different reaction conditions (temperature, solvent and base). In particular, the latter reacted with 3 in toluene at 10°C, in the presence of t-butyllitium, giving (3S,1′S)-N-methyl-N-(1′-phenylethyl)-1,3-dimethyl-5-methoxyoxindol-3-ilacetamide (10) with a 63% d.e.. This intermediate was easily separated from the undesired minor (3R,1′S) diastereomer (11) and converted to (-)-esermethole (99.6% e.e.) in two steps.