Enantioselective synthesis of (R)-salmeterol employing an asymmetric Henry reaction as the key step

A practical synthesis of (R)-salmeterol has been accomplished from 3-bromo salicylaldehyde, which involved a Cu(II)–sparteine complex catalyzed asymmetric Henry reaction as the key step. (R)-Salmeterol can be obtained in 39% overall yield and 95% ee.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-nitroethanolC12H15NO5Ee = 96%[α]D25=-33.1 (c 1.0, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(6-(4-phenylbutoxy)hexylamino)ethanolC28H41NO4Ee = 95%[α]D25=-13.2 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-4-(1-Hydroxy-2-(6-(4-phenylbutoxy)hexylamino)ethyl)-2-(hydroxymethyl)phenolC25H37NO4Ee = 95%[α]D25=-19.1 (c 0.37, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)