Supplementary Material
Direct Asymmetric Aldol Reaction of Cyclohexanone
with Aldehydes Catalyzed by Chiral
trans-Cyclohexanediamine L-tartrate Salt
Shengying Wu ● Limin Wang ● Jun Tang ● Dan Mao ● Xin
Liu
General Information: Unless otherwise stated, materials were purchased from commercial
suppliers and used without purification. 1H NMR spectra was recorded on a Varian 400 (400 MHz)
spectrophotometers. Flash column chromatography was performed using 200-300 mesh silica gel.
Chiral HPLC was performed on Waters 2487 series with chiral columns (Chiralcel AD-H/OD-H).
General procedure for asymmetric aldol reaction
Aromatic aldehyde (0.5 mmol) was introduced to a mixture of a catalytic amount of catalyst (0.05
mmol, 10 mol %) and neat cyclohexone (2.0 mmol) in the mixture of 4/1 EtOH-brine (0.10 mL)
co-solvent. The reaction mixture was stirred at room temperature for the time indicated in Table 3.
The catalyst was recycled with simply filtration. The reaction mixture was subsequently filtered,
extracted with ethyl acetate and dried over anhydrous Na2SO4. The organic layers were evaporated
under reduced pressure. The crude aldol product was purified by flash column on a silica gel
chromatography to afford the aldol adducts as a white/ pale-yellow solid, and then determined by
1H NMR spectroscopy and chiral HPLC.
Gerneral procedure for racemic samples
Electron-withdrawing aromatic aldehyde (0.5 mmol), neat ketone and weak base additives (TEA,
EDA, or K2CO3 if necessary) was magnetically stirred in one-pot in 4/1 EtOH-brine co-solvent at
room temperature for 48h. The reaction mixture was filtered and extracted with ethyl acetate, and
then dried over anhydrous Na2SO4. The organic layers were evaporated under reduced pressure.
The crude residue was purified by flash column, and determined by chiral HPLC.
Enantioseparation of aldol products
All the syn/anti isomers have been compared with literature report, the retention times were
determined by racemate which was obtained by literature procedure. And all the HPLC datas
(diastereomeric ratio) were also in accordance with 1H NMR.
1H
NMR and HPLC data for aldol products
OH
O
OH
O
：
O 2N
O2 N
ant i (major)
70
syn ( minor)
：
30
2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one Anti/syn=70/30, 1H NMR (400 MHz,
CDCl3) δ(ppm) 1.50-1.88 (m, 5H), 2.09-2.15 (m, 1H), 2.32-2.44 (m, 1H), 2.48-2.52 (m, 1H),
2.56-2.66 (m, 1H), 3.18 (syn-OH, s, 1H), 4.07 (anti-OH, d, J=3.2 Hz, 1H), 4.90 (anti-CH*OH, dd,
J=2.8 Hz, 8.2 Hz, 1H), 5.49 (syn-CH*OH, s, 1H), 7.50 (t, J=8.0 Hz, 8.4 Hz, 2H), 8.21 (d, J=8.0
Hz, 2H); Enantiomeric excess was determined by HPLC on a chiral stationary phase using a
Chiralcel AD-H column (90:10 Hexane: i-PrOH), 1.0 mL/min, λ=254 nm; syn-enantiomer (minor):
tR=21.5 min (major syn-product) and 24.6 min; anti-enantiomer (major): tR=27.3 min (major
anti-product) and 36.6 min.
OH
O
OH
O
：
NO 2
NO2
ant i (major)
syn ( minor)
：
99
1
2-(Hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one Anti/syn=99/1, 1H NMR (400 MHz,
CDCl3) δ(ppm) 1.54-1.79 (m, 5H), 2.08-2.12 (m, 1H), 2.30-2.38 (m, 1H), 2.44-2.48 (m, 1H),
2.73-2.79 (m, 1H), 3.28 (syn-OH, s, 1H), 4.19 (anti-OH, d, J=4.4Hz, 1H), 5.45 (anti-CH*OH, dd,
J=3.2 Hz, 6.8 Hz, 1H), 5.96 (syn-CH*OH, s, 1H), 7.43 (t, J=7.2 Hz, 8.0 Hz, 1H), 7.64 (t, J=7.2
Hz, 7.2 Hz,1H), 7.77 (d, J=7.2 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H); Enantiomeric excess was
determined by HPLC on a chiral stationary phase using a Chiralcel AD-H column (90:10 Hexane:
i-PrOH), 0.9 mL/min, λ=254 nm; syn-enantiomer (minor): tR=15.5 min (major syn-product) and
17.0 min; anti-enantiomer (major): tR=24.4 min and 26.5 min (major anti-product).
OH
O
OH
O
：
NO2
NO 2
anti ( major)
syn (minor)
：
74
26
2-(Hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one Anti/syn=74/26, 1H NMR (400 MHz,
CDCl3) δ(ppm) 1.52-1.89 (m, 5H), 2.09-2.15 (m, 1H), 2.34-2.45 (m, 1H), 2.48-2.53 (m, 1H),
2.59-2.68 (m, 1H), 3.18 (syn-OH, s, 1H), 4.11 (anti-OH, d, J=3.2 Hz, 1H), 4.90 (anti-CH*OH, dd,
J=2.8 Hz, 8.4 Hz, 1H), 5.48 (syn-CH*OH, s, 1H), 7.50-7.68 (m, 2H), 8.11-8.21 (m, 2H);
Enantiomeric excess was determined by HPLC on a chiral stationary phase using a Chiralcel
AD-H column (95:5 Hexane: i-PrOH), 1.0 mL/min, λ=254 nm; syn-enantiomer (minor): tR=38.9
min (major syn-product) and 42.9 min; anti-enantiomer (major): tR=48.4 min and 64.0 min(major
anti-product).
OH
O
OH
O
：
NC
NC
ant i (major)
60
syn ( minor)
：
40
2-(Hydroxy(4-cyanophenyl)methyl)cyclohexan-1-one Anti/syn=60/40, 1H NMR (400 MHz,
CDCl3) δ(ppm) 1.50-1.88 (m, 5H), 2.08-2.14 (m, 1H), 2.32-2.43 (m, 1H), 2.47-2.52 (m, 1H),
2.54-2.63 (m, 1H), 3.16 (syn-OH, d, J=3.2 Hz, 1H), 4.06 (anti-OH, d, J=3.2 Hz, 1H), 4.84
(anti-CH*OH, dd, J=3.2 Hz, 8.4 Hz, 1H), 5.43 (syn-CH*OH, s, 1H), 7.42-7.46 (m, 2H), 7.63-7.66
(m, 2H); Enantiomeric excess was determined by HPLC on a chiral stationary phase using a
Chiralcel AD-H column (90:10 Hexane: i-PrOH), 0.9 mL/min, λ=254 nm; syn-enantiomer (minor):
tR=19.2 min (major syn-product) and 22.5 min; anti-enantiomer (major): tR=25.8 min (major
anti-product) and 32.7 min.
OH
O
OH
O
：
F 3C
F3 C
ant i (major)
syn ( minor)
：
56
44
2-(Hydroxy(4-trifluoromethylphenyl)methyl)cyclohexan-1-one
Anti/syn=56/44, 1H NMR
(400 MHz, CDCl3) δ(ppm) 1.49-1.88 (m, 5H), 2.08-2.14 (m, 1H), 2.32-2.43 (m, 1H), 2.45-2.52
(m, 1H), 2.56-2.63 (m, 1H), 3.10 (syn-OH, d, J=3.2 Hz, 1H), 4.03 (anti-OH, d, J=2.8 Hz, 1H),
4.84 (anti-CH*OH, dd, J=2.8 Hz, 8.4 Hz, 1H), 5.44 (syn-CH*OH, s, 1H), 7.42-7.46 (m, 2H),
7.59-7.62 (m, 2H); Enantiomeric excess was determined by HPLC on a chiral stationary phase
using a Chiralcel AD-H column (90:10 Hexane: i-PrOH), 0.9 mL/min, λ=215 nm; syn-enantiomer
(minor): tR= 8.9 min (major syn-product) and 10.2 min; anti-enantiomer (major): tR=13.0 min
(major anti-product) and 16.1 min.
OH
O
OH
O
：
CF3
CF 3
anti ( major)
99
syn (minor)
：
1
2-(Hydroxy(2-trifluoromethylphenyl)methyl)cyclohexan-1-one Anti/syn>99/1, 1H NMR (400
MHz, CDCl3) δ(ppm) 1.39-1.80 (m, 5H), 2.06-2.12 (m, 1H), 2.33-2.42 (m, 1H), 2.48-2.53 (m,
1H), 2.72-2.79 (m, 1H), 4.02 (anti-OH, d, J=3.2 Hz, 1H), 5.30 (anti-CH*OH, dd, J=1.2 Hz, 12.8
Hz, 1H), 7.38-7.42 (m, 1H), 7.58-7.65 (m, 2H), 7.70-7.72 (m, 1H); Enantiomeric excess was
determined by HPLC on a chiral stationary phase using a Chiralcel AD-H column (90:10 Hexane:
i-PrOH), 0.9 mL/min, λ=215 nm; anti-enantiomer (major): tR= 14.0 min and 14.9 min (major
anti-product).
Copies of 1H NMR and HPLC spectra for direct asymmetric aldol reaction
OH
O
OH
O
：
O 2N
O2 N
ant i (major)
70
1
H NMR Spectra
HPLC Spectra
syn ( minor)
：
30
Racemic sample
Chiral sample
OH
O
OH
O
：
NO 2
NO2
ant i (major)
99
1
H NMR Spectra
syn ( minor)
：
1
HPLC Spectra
Racemic sample
Chiral sample
OH
O
OH
O
：
NO2
NO 2
anti ( major)
syn (minor)
74
1
H NMR Spectra
：
26
HPLC Spectra
Racemic sample
Chiral sample
OH
O
OH
O
：
NC
NC
ant i (major)
60
1
H NMR Spectra
syn ( minor)
：
40
HPLC Spectra
Racemic sample
Chiral sample
OH
O
OH
O
：
F 3C
F3 C
ant i (major)
56
1
H NMR Spectra
syn ( minor)
：
44
HPLC Spectra
Racemic sample
Chiral sample
OH
O
OH
O
：
CF3
CF 3
anti ( major)
99
1
H NMR Spectra
syn (minor)
：
1
HPLC Spectra
Racemic sample
Chiral sample