Enantioselective synthesis of (S,S)-ethambutol using proline-catalyzed asymmetric α-aminooxylation and α-amination

An efficient enantioselective synthesis of (S,S)-ethambutol, a tuberculostatic antibiotic, has been achieved in 99% ee via both proline-catalyzed α-aminooxylation and α-amination of n-butyraldehyde as the key step.

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(R)-2-N-Phenylaminooxy(tert-butyl)dimethylsilaneC16H29NO2Si[α]D25=+42.35 (c 1, CHCl3)Source of chirality: α-aminooxylationAbsolute configuration: R

((R)-2-Hydroxy)(tert-butyl)dimethylsilaneC10H24O2Si[α]D25=-9.4 (c 1, CHCl3)Source of chirality: α-aminooxylationAbsolute configuration: R

(R)-1-(tert-Butyldimethylsilyloxybutan-3-yl) 4-methylbenzenesulfonateC17H30O4SSi[α]D25=+17.0 (c 1, CHCl3)Source of chirality: α-aminooxylationAbsolute configuration: R

((S)-2-Azidobutoxy)(tert-butyl)dimethylsilaneC10H23N3OSi[α]D25=+21.9 (c 1, CHCl3)Source of chirality: α-aminooxylationAbsolute configuration: S

((S)-2-Aminobutoxy)(tert-butyl)dimethylsilaneC10H25NOSi[α]D25=+9.1 (c 1, CHCl3)Source of chirality: α-aminooxylationAbsolute configuration: S

(S)-2-(1, 2-Dibenzyloxycarbonylhydrazinyl)-1-butanolC20H24N2O5[α]D25=+14.3 (c 1, CHCl3)Source of chirality: α-aminationAbsolute configuration: S

(S,S)-N1,N2-Bis(1-tert-butyldimethylsilyloxybutan-3- yl)oxamideC22H48N2O4Si2[α]D25=-60.3 (c 1, CHCl3)Source of chirality: α-aminationAbsolute configuration: S,S