Application of amide-stabilized sulfur ylide reactivity to the stereodivergent synthesis of (R,S)- and (S,R)-reboxetine

A simple access to (R,S)- and (S,R)-reboxetine from a single chiral sulfonium salt 4 is reported. This approach, based on a stabilized sulfur ylide-mediated epoxidation, followed by a regioselective opening reaction, enables the preparation of these two potentially biologically active compounds in 35.6% and 13.7% overall yield.

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(1′S,2S,3S)-(−)3-(2-Ethoxy-phenoxy)-2-hydroxy-3-phenyl-N-(1′-phenyl-ethyl)-propionamideC25H27NO4[α]D20=-46.0 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2S,3S)

(1′S,2R,3R)-(−)-3-(2-Ethoxy-phenoxy)-2-hydroxy-3-phenyl-N-(1′-phenyl-ethyl)-propionamideC25H27NO4[α]D20=-26.5 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2R,3R)

(1′S,2R,3S)-(−)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(1′-phenyl-ethylamino)-propan-2-olC25H29NO3[α]D20=-23.4 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2R,3S)

(1′S,2S,3R)-(−)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(1-phenyl-ethylamino)-propan-2-olC25H29NO3[α]D20=-18.2 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2S,3R)

(1′S,6R)-(+)-6-[(S)-(2-Ethoxy-phenoxy)-phenyl-methyl]-4-(1′-phenyl-ethyl)-morpholin-3-oneC27H29NO4[α]D20=+4.8 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,6R, S)

(1′S,6S)-(−)-6-[(R)-(2-Ethoxy-phenoxy)-phenyl-methyl]-4-(1′-phenyl-ethyl)-morpholin-3-oneC27H29NO4[α]D20=-102.6 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,6S,R)

(1′S,2R,2aS)-(−)-2-[(2-Ethoxy-phenoxy)-phenyl-methyl]-4-(1′-phenyl-ethyl)-morpholineC27H31NO3[α]D20=-5.5 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2R,2aS)

(1′S,2S,2aR)-(−)-2-[(2-Ethoxy-phenoxy)-phenyl-methyl]-4-(1′-phenyl-ethyl)-morpholineC27H31NO3[α]D20=-18.5 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (1′S,2S,2aR)

(2R)-(+)-2-[(S)-(2-Ethoxy-phenoxy)-phenyl-methyl]-morpholine, ReboxetineC19H23NO3[α]D20=+16.1 (c 1.0, CH2Cl2)Source of chirality: (S)-phenylethylamineAbsolute configuration: (2R,S)