A convenient synthesis of (R)-salmeterol via Rh-catalyzed asymmetric transfer hydrogenation

(R)-Salmeterol was synthesized in eight steps with salicaldehyde as the starting material. The key chiral intermediate, alcohol 5, was prepared via Rh-catalyzed asymmetric transfer hydrogenation with (S,S)-PEG-BsDPEN or (S,S)-TsDPEN ligand and sodium formate as the hydrogen donor under mild conditions.

(R)-Salmeterol was synthesized in eight steps with salicaldehyde as the starting material. The key chiral intermediate was prepared via Rh-catalyzed asymmetric transfer hydrogenation under mild conditions.Figure optionsDownload as PowerPoint slide

(R)-2-Bromo-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanolC12H15BrO3Ee = 98%[α]D20=-29.3 (c 1.1, CHCl3)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-2,2-Dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxineC12H14O3[α]D20=-39.7 (c 1.1, CHCl3)Source of chirality: (R)-2-bromo-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanolAbsolute configuration: (R)

(R)-2-(Benzyl(6-(4-phenylbutoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanolC35H47NO4[α]D20=-13.9 (c 1.1, CHCl3)Source of chirality: (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxineAbsolute configuration: (R)

(R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(6-(4-phenylbutoxy)hexylamino)ethanolC28H41NO4[α]D20=-16.5 (c 1.2, CHCl3)Source of chirality: (R)-2-(benzyl(6-(4-phenylbutoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanolAbsolute configuration: (R)

(R)-4-(1-Hydroxy-2-(6-(4-phenylbutoxy)hexylamino)ethyl)-2-(hydroxymethyl)phenolC25H37NO4[α]D20=−18.7 (c 1.06, MeOH)Source of chirality: (R)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(6-(4-phenylbutoxy)hexylamino)ethanolAbsolute configuration: (R)