Asymmetric Mannich reaction catalyzed by N-arylsulfonyl-l-proline amides

Proline-derived N-sulfonylcarboxamides efficiently catalyze the asymmetric Mannich reaction of cyclic ketones with N-(p-methoxyphenyl)-protected iminoglyoxylate. Both classical organic solvents and ionic liquids were used as the reaction media. With cyclohexanone, the reaction proceeded with high enantioselectivity (99% ee). Enamine intermediates were investigated by DFT calculations.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(S)-N-4-Butylbenzenesulfonyl-l-proline amideC15H22N2O3S[α]D = −29.1 (c 1.0, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S)

(2S,1′S)-Ethyl-2-(4-methoxyphenylamino)-2-(2′-oxocyclohex-1′-yl)-acetateC17H23NO4Ee >99%[α]D = −40.3 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,1′S)

(2S,1′S)-Ethyl-2-(4-methoxyphenylamino)-2-(2′-oxocyclobut-1′-yl)-acetateC15H19NO4Ee = 69%[α]D = −28.3 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,1′S)

(2S,1′S)-Ethyl-2-(4-methoxyphenylamino)-2-(2′-oxocyclohept-1′-yl)-acetateC18H25NO4Ee = 75%[α]D = −18.3 (c 0.1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,1′S)