Asymmetric synthesis of 1,4-amino alcohol ligands with a norbornene backbone for use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-amino alcohols with a norbornene backbone was performed starting with (2S,3R)-(−)-cis-hemiester 2 (98% ee). Chemoselective amination with NH4OH and HMPTA followed by LAH reduction afforded 5 and 7, respectively. Amido ester 6 was transformed into chiral ligand 9 with Grignard reaction followed by LAH reduction. The chiral ligands 5, 7, and 9 were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, chiral ligand 7 exhibited the highest enantioselectivity (88% ee).

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(2S,3R)-2-Carboxamido-3-methoxycarbonylbicyclo[2.2.1]hept-5-eneC10H13NO3Ee = 98%[α]D20=-2.5 (c 2.77, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R

(2S,3R)-2-Aminomethyl-3-hydroxymethylbicyclo[2.2.1]hept-5-eneC9H15NOEe = 98%[α]D20=-8.9 (c 0.56, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R

(2S,3R)-2-(N,N-Dimethylcarboxamido)-3-methoxycarbonylbicyclo[2.2.1]hept-5-eneC12H17NO3Ee = 98%[α]D20=-35.7 (c 1.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R

(2S,3R)-2-Dimethylaminomethyl-3-hydroxymethylbicyclo[2.2.1]hept-5-eneC11H19NOEe = 98%[α]D20=+15.1 (c 1.16, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R

(2S,3R)-2-(N,N-Dimethylcarboxamino)-3-(diphenylhydroxymethyl)bicyclo[2.2.1]hept-5-eneC23H25NO2Ee = 98%[α]D20=+8.3 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R

(2S,3R)-2-(Dimethylaminomethyl)-3-(diphenylhydroxymethyl)bicyclo[2.2.1]hept-5-eneC23H27NOEe = 98%[α]D20=-17.8 (c 0.56, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: 2S,3R