Synthesis of (S)-(+)-sotalol and (R)-(−)-isoproterenol via a catalytic enantioselective Henry reaction

A unified approach for the synthesis of (S)-(+)-sotalol and (R)-(−)-isoproterenol has been developed. The enantioselective Henry reaction of the appropriate aldehyde in the presence of a camphor-derived amino pyridine–Cu(II) complex was the key step of the synthesis. The reduction of the nitro group to give the corresponding amino alcohols followed by reductive alkylation of the amine provided the target products with high enantiomeric excesses.

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(S)-(+)-N-[4-(1-Hydroxy-2-nitroethyl)phenyl]methanesulfonamideC9H12N2O5SEe = 92%[α]D25=+19.5 (c 0.54, MeOH)Source of chirality: enantioselective synthesisAbsolute configuration: (S)

(S)-(+)-N-[4-(2-Amino-1-hydroxyethyl)phenyl]methanesulfonamideC9H14N2O3SEe = 92%[α]D25=+23.6 (c 1.03, MeOH)Source of chirality: enantioselective synthesisAbsolute configuration: (S)

(S)-(+)-SotalolC12H20N2O3SEe = 92%[α]D25=+19.3 (c 0.27, MeOH)Source of chirality: enantioselective synthesisAbsolute configuration: (S)

(S)-(+)-Sotalol hydrochlorideC12H20N2O3S·HClEe = 92%[α]D25=+28.7 (c 1.05, H2O)Source of chirality: enantioselective synthesisAbsolute configuration: (S)

(R)-(−)-1-(3,4-Dimethoxyphenyl)-2-nitroethanolC10H13NO5Ee = 96%[α]D25=-27.1 (c 2.01, CH2Cl2)Source of chirality: enantioselective synthesisAbsolute configuration: (R)

(R)-(−)-2-Amino-1-(3,4-dimethoxyphenyl)ethanolC10H15NO3Ee = 96%[α]D25=-24.0 (c 1.08, EtOH)Source of chirality: enantioselective synthesisAbsolute configuration: (R)

(R)-(−)-1-(3,4-Dimethoxyphenyl)-2-(isopropylamino)ethanolC10H15NO3Ee = 96%[α]D25=-32.7 (c 3.00, acetone)Source of chirality: enantioselective synthesisAbsolute configuration: (R)