Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(−)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respectively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).

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(2S,3R)-3-(2-Hydroxypropan-2-yl)-N,N-dimethylbicyclo[2.2.1]hept-5-ene-2-carboxamideC13H21NO2C13H21NO2Ee = 98%[α]D20=+84.6(c1.84,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

(2S,3R)-3-(3-Hydroxypentan-3-yl)-N,N-dimethylbicyclo[2.2.1]hept-5-ene-2-carboxamideC15H25NO2C15H25NO2Ee = 98%[α]D20=+80.8(c2.11,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

(2S,3R)-3-(1-Hydroxycyclopentyl)-N,N-dimethylbicyclo[2.2.1]hept-5-ene-2-carboxamideC15H23NO2C15H23NO2Ee = 98%[α]D20=+46.2(c2.01,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

(2S,3R)-3-(1-Hydroxycyclohexyl)-N,N-dimethylbicyclo[2.2.1]hept-5-ene-2-carboxamideC16H25NO2C16H25NO2Ee = 98%[α]D20=+52.4(c2.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

2-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)propan-2-olC13H23NOC13H23NOEe = 98%[α]D20=+17.4(c1.37,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

3-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)pentan-3-olC15H27NOC15H27NOEe = 98%[α]D20=+17.35(c1.30,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

1-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)cyclopentanolC15H25NOC15H25NOEe = 98%[α]D20=+11.1(c2.56,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

1-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)cyclohexanolC16H27NOC16H27NOEe = 98%[α]D20=+3.7(c2.16,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(2R,3S)-Methyl 3-(diethylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC14H21NO3C14H21NO3Ee = 98%[α]D20=-32.4(c3.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

(2R,3S)-Methyl 3-(diallylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC16H21NO3C16H21NO3Ee = 98%[α]D20=-43.9(c2.03,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(dibenzylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC24H25NO3C24H25NO3Ee = 98%[α]D20=-34.9(c2.03,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(pyrrolidine-1-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC14H19NO3C14H19NO3Ee = 98%[α]D20=-24.65(c0.10,MeOH)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(piperidine-1-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC15H21NO3C15H21NO3Ee = 98%[α]D20=-21.95(c2.00,MeOH)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(morpholine-4-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC14H19NO4C14H19NO4Ee = 98%[α]D20=-32.2(c0.20,MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC13H23NOC13H23NOEe = 98%[α]D20=-6.4(c1.80,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-((Diallylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC15H23NOC15H23NOEe = 98%[α]D20=+15.7(c1.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-((Dibenzylamino)methyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC23H27NOC23H27NOEe = 98%[α]D20=-33.0(c2.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-(Pyrrolidin-1-ylmethyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC13H21NOC13H21NOEe = 98%[α]D20=+1.6(c2.00,MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-(Piperidin-1-ylmethyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC14H23NOC14H23NOEe = 98%[α]D20=-3.6(c2.00,MeOH)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

((2R,3S)-3-(Morpholinomethyl)bicyclo[2.2.1]hept-5-en-2-yl)methanolC13H21NO2C13H21NO2Ee = 98%[α]D20=-4.3(c2.00,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(2-nitrophenylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC16H16N2O5C16H16N2O5Ee = 98%[α]D20=+7.9(c2.00,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(2-chlorophenylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC16H16ClNO3C16H16ClNO3Ee = 98%[α]D20=+58.9(c2.00,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

(2R,3S)-Methyl 3-(tosylcarbamoyl)bicyclo[2.2.1]hept-5-ene-2-carboxylateC17H19NO5SC17H19NO5SEe = 98%[α]D20=+16.7(c2.00,CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R,3S)

((2R,3S)-3-((2-Aminophenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)methanolC15H22N2OC15H22N2OEe = 98%[α]D20=-116.0(c0.10,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-((Phenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)methanolC15H21NOC15H21NOEe = 98%[α]D20=+5.1(c2.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

((2R,3S)-3-((2-Chlorophenylamino)methyl)bicyclo[2.2.1]heptan-2-yl)methanolC15H20ClNOC15H20ClNOEe = 98%[α]D20=+10.8(c2.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)

N-(((2S,3R)-3-(Hydroxymethyl)bicyclo[2.2.1]heptan-2-yl)methyl)-4-methylbenzenesulfonamideC16H23NO3SC16H23NO3SEe = 98%[α]D20=-13.2(c1.00,CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)