Chemoenzymatic syntheses of novel ligands derived from trans-cyclohexane-1,2-diamine: application in the enantioselective addition of diethylzinc to aromatic aldehydes

Enantiopure (1R,2R)-cyclohexane-1,2-diamine derivatives, easily prepared from the corresponding (±)-trans-2-dialkylaminocyclohexanols through a chemoenzymatic route, have been employed as ligands in the enantioselective addition of diethylzinc to aromatic aldehydes. Of all the ligands tested, C2-symmetric bisaminoamides derived from pyridine-2,6-dicarboxylic acid proved to be the most efficient.

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(1R,2R)-N-[2-(Morpholin-4-yl)cyclohexyl]benzamideC17H24N2O2Ee >99%[α]D20=-93.7 (c 0.70, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)

(1R,2R)-N-[2-(N′-Isopropyl-N′-methylamino)cyclohexyl]benzamideC17H26N2OEe >99%[α]D20=-13.1 (c 0.70, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)

tert-Butyl (1R,2R)-N-[2-(morpholin-4-yl)cyclohexyl]carbamateC15H28N2O3Ee >99%[α]D20=-51.6 (c 0.80, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)

tert-Butyl (1R,2R)-N-[2-(N′-isopropyl-N′-methylamino)cyclohexyl]carbamateC15H30N2O2Ee >99%[α]D20=-112.5 (c 0.70, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)

(1R,2R)-N-[2-(Morpholin-4-yl)cyclohexyl]pyridine-2-carboxamideC16H23N3O2Ee >99%[α]D20=-79.2 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(morpholin-4-yl)cyclohexyl]benzene-1,5-dicarboxamideC28H42N4O4Ee >99%[α]D20=-98.9 (c 0.67, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(morpholin-4-yl)cyclohexyl]pyridine-2,6-dicarboxamideC27H41N5O4Ee >99%[α]D20=-167.0 (c 0.60, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-{2-[isopropyl(methyl)amino]cyclohexyl}benzene-1,5-dicarboxamideC28H46N4O2Ee >99%[α]D20=-111.1 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-{2-[isopropyl(methyl)amino]cyclohexyl}pyridine-2,6-dicarboxamideC27H45N5O2Ee >99%[α]D20=-183.8 (c 0.93, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(piperidin-1-yl)cyclohexyl]benzene-1,5-dicarboxamideC30H46N4O2Ee >99%[α]D20=-130.7 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(piperidin-1-yl)cyclohexyl]pyridine-2,6-dicarboxamideC29H45N5O2Ee >99%[α]D20=-186.9 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(pyrrolidin-1-yl)cyclohexyl]benzene-1,5-dicarboxamideC28H42N4O2Ee >99%[α]D20=-84.9 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,1″R,2′R,2″R)

(1′R,1″R,2′R,2″R)-N,N′-Bis-[2-(pyrrolidin-1-yl)cyclohexyl]pyridine-2,6-dicarboxamideC27H41N5O2Ee >99%[α]D20=-117.8 (c 0.50, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R,2R)