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H. Tian et al. / Tetrahedron: Asymmetry 22 (2011) 1074–1080
4.2.1. (S)-2-Amino-N-(4-(piperidin-1-yl)pyridin-3-yl)propan-
J = 9.0 Hz, 1H), 4.02 (br s, 1H), 2.58–2.26 (m, 3H), 2.10–2.03 (m,
amide 5a
1H), 1.81–1.30 (m, 5H).
Yield: 89%; colorless oil, ½a D25
ꢁ
¼ þ16:5 (c 0.2, CHCl3), 1H NMR
(CDCl3, 300 MHz), d: 9.81 (br s, 1H), 9.48 (s, 1H), 8.26 (d,
J = 6.9 Hz, 1H), 6.92 (d, J = 5.4 Hz, 1H), 3.73–3.66 (m, 1H), 2.90–
2.87 (m, 4H), 1.83–1.72 (m, 6H), 1.46 (d, J = 6.9 Hz, 3H). 13C NMR
(CDCl3, 75 MHz), d: 173.5, 149.7, 145.4, 141.5, 128.6, 113.8, 51.8,
51.2, 25.9, 23.8, 21.5.
4.3.2. 2-(Hydroxy(3-nitrophenyl)methyl)cyclohexanone 6b
Yield: 99%; anti/syn >99:1. Enantiomeric excess: 94% of anti-dia-
stereomer determined by HPLC analysis Chiralcel AD-H (i-PrOH/
hexane = 5:95), UV 254 nm, flow rate 1.0 mL/min. tR = 37.2 min
(anti, major) and tR = 48.1 min (anti, minor). 1H NMR (CDCl3,
300 MHz), d: 8.23 (t, J = 3.6 Hz, 1H), 8.19–8.16 (m, 1H), 7.70 (d,
J = 9.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 4.92 (d, J = 9.0 Hz, 1H), 4.11
(br s, 1H), 2.67–2.32 (m, 3H), 2.17–2.09 (m, 1H), 1.86–1.36 (m, 5H).
4.2.2. (S)-2-Amino-N-(4-(piperidin-1-yl)pyridin-2-yl)propan-
amide 5b
Yield: 82%; colorless oil, ½a D25
ꢁ
¼ ꢂ15:3 (c 0.2, CHCl3), 1H NMR
(CDCl3, 300 MHz), d: 7.90 (d, J = 6.3 Hz, 1H), 7.74 (d, J = 3.6 Hz,
1H), 6.40–6.37 (m, 1H), 3.60–3.53 (m, 1H), 3.36–3.29 (m, 4H),
1.64–1.56 (m, 6H), 1.39 (d, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz), d: 174.7, 156.6, 152.2, 148.0, 104.9, 97.1, 51.2, 47.3,
25.1, 24.2, 21.4.
4.3.3. 2-(Hydroxy(2-nitrophenyl)methyl)cyclohexanone 6c
Yield: 99%; anti/syn >99:1. Enantiomeric excess: 96% of anti-dia-
stereomer determined by HPLC analysis Chiralcel OD-H (i-PrOH/
hexane = 5:95), UV 254 nm, flow rate 1.0 mL/min. tR = 16.1 min
(anti, major) and tR = 20.1 min (anti, minor). 1H NMR (CDCl3,
300 MHz), d: 7.83 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.62
(t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), (d, J = 6.0 Hz, 1H), 4.13
(br s, 1H), 2.75–2.67 (m, 1H), 2.40–2.88 (m, 2H), 2.09–2.00 (m,
1H), 1.72–1.56 (m, 5H).
4.2.3. (S)-N-((S)-1-Oxo-1-((4-(piperidin-1-yl)pyridin-3-yl)amino)-
propan-2-yl)pyrrolidine-2-carboxamide 2
Yield: 64%; White solid, mp 52–54 °C, ½a D25
¼ ꢂ230:2 (c 0.2,
ꢁ
CHCl3), 1H NMR (CDCl3, 300 MHz), d: 9.36 (s, 1H), 8.33 (s, 1H),
8.29 (d, J = 6.0 Hz, 1H), 8.21 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 6.0 Hz,
1H), 4.70–4.59 (m, 1H), 3.85–3.80 (m, 1H), 3.11–2.80 (m, 6H),
2.28–2.07 (m, 3H), 2.01–1.92 (m, 1H), 1.79–1.73 (m, 6H), 1.50 (d,
J = 9.0 Hz, 3H). 13C NMR (CDCl3, 75 MHz), d: 175.1, 170.0, 150.3,
145.8, 142.6, 128.3, 114.0, 60.1, 51.9, 48.8, 46.9, 30.5, 25.9, 25.8,
23.7, 17.6. (EI) m/z 346 (rel intensity) (M++1); Anal. Calcd for
(C18H27N5O2): C, 62.58; H, 7.88; N, 20.27; O, 9.26. Found: C,
62.51; H, 7.63; N, 20.51; O, 9.30.
4.3.4. 2-(Hydroxy(4-cyanophenyl)methyl)cyclohexanone 6d
Yield: 99%; anti/syn = 98:2. Enantiomeric excess: 97% of anti-
diastereomer determined by HPLC analysis Chiralcel OD-H (i-
PrOH/hexane = 5:95), UV 220 nm, flow rate 1.0 mL/min.
tR = 26.3 min (anti, major) and tR = 39.4 min (anti, minor). 1H
NMR (CDCl3, 300 MHz), d: 7.67 (d, J = 8.1 Hz, 2H), 7.47 (d,
J = 8.1 Hz, 2H), 4.85 (d, J = 8.4 Hz, 1H), 4.05 (br s, 1H), 2.61–2.47
(m, 2H), 2.41–2.30 (m, 1H), 2.14–2.09 (m, 1H), 1.85–1.34 (m, 5H).
4.2.4. (S)-N-((S)-1-Oxo-1-((4-(piperidin-1-yl)pyridin-2-yl)amino)-
4.3.5. 2-(Hydroxy(3-cyanophenyl)methyl)cyclohexanone 6e
Yield: 96%; anti/syn >99:1. Enantiomeric excess: 95% of anti-dia-
stereomer determined by HPLC analysis Chiralcel OD-H (i-PrOH/
hexane = 5:95), UV 220 nm, flow rate 1.0 mL/min. tR = 23.2 min
(anti, major) and tR = 31.1 min (anti, minor). 1H NMR (CDCl3,
300 MHz), d: 7.65 (s, 1H), 7.61 (t, J = 6.6 Hz, 2H), 7.49 (t,
J = 7.6 Hz, 1H), 4.83 (d, J = 8.7 Hz, 1H), 4.04 (br s, 1H), 2.62–2.49
(m, 2H), 2.42–2.39 (m, 1H), 2.16–2.08 (m, 1H), 1.86–1.80 (m,
1H), 1.69–1.50 (m, 3H), 1.42–1.31 (m, 1H).
propan-2-yl)pyrrolidine-2-carboxamide 3
Yield: 60%; White solid, mp 56–58 °C, ½a D25
¼ ꢂ94:9 (c 0.2,
ꢁ
CHCl3), 1H NMR (CDCl3, 300 MHz), d: 8.96 (s, 1H), 8.20–8.13 (m,
1H), 7.91–7.89 (m, 1H), 7.71–7.68 (m, 1H), 6.45–6.42 (m, 1H),
4.66–4.56 (m, 1H), 3.85–3.81 (m, 1H), 3.42–3.32 (m, 4H), 3.08–
2.89 (m, 2H), 2.21–2.14 (m, 1H), 1.96–1.88 (m, 1H), 1.78–1.69
(m, 2H), 1.67–1.61 (m, 6H), 1.47 (d, J = 6.0 Hz, 3H). 13C NMR (CDCl3,
75 MHz), d: 175.2, 171.4, 156.4, 152.5, 147.5, 104.9, 97.6, 60.4,
48.8, 47.2, 47.1, 30.7, 26.0, 24.9, 24.2, 18.3. (EI) m/z 346 (rel inten-
sity) (M++1); Anal. Calcd for (C18H27N5O2): C, 62.58; H, 7.88; N,
20.27; O, 9.26. Found: C, 62.54; H, 7.67; N, 20.41; O, 9.37.
4.3.6. 2-(Hydroxy(2-cyanophenyl)methyl)cyclohexanone 6f
Yield: 97%; anti/syn >99:1. Enantiomeric excess: 96% of anti-dia-
stereomer determined by HPLC analysis Chiralcel OD-H (i-PrOH/
hexane = 5:95), UV 220 nm, flow rate 1.0 mL/min. tR = 15.1 min
(anti, major) and tR = 18.1 min (anti, minor). 1H NMR (CDCl3,
300 MHz), d: 7.66–7.63 (m, 3H), 7.45–7.38 (m, 1H), 5.25 (d,
J = 8.4 Hz, 1H), 4.25 (br s, 1H), 2.73–2.64 (m, 1H), 2.55–2.42 (m,
1H), 2.31–2.30 (m, 1H), 2.15–2.07 (m, 1H), 1.87–1.82 (m, 1H),
1.58–1.54 (m, 4H).
4.3. General procedure for the catalytic direct asymmetric aldol
reaction
The aldol reactions were carried out in a closed glass reactor. A
mixture of the aldehyde (0.25 mmol), cyclohexanone (1.25 mmol),
catalyst (10 mol %), 4-dinitrophenol (DNP) (10 mol %) and brine
(1.0 mL) was stirred at room temperature until all of the aldehyde
had been consumed (monitored by TLC). Then the reaction was
quenched with saturated ammonium chloride solution (5 mL),
and extracted with ethyl acetate (10 mL ꢀ 3). The combined organ-
ic layer was washed with saturated NaHCO3 solution and dried
over anhydrous Na2SO4. After the removal of the solvent under re-
duced pressure, the residue was purified through flash column
chromatography on silica gel (ethyl acetate/petroleum ether, 1:3)
to give the pure product.
4.3.7. 2-(Hydroxy(3-chlorophenyl)methyl)cyclohexanone 6g
Yield: 97%; anti/syn = 98:2. Enantiomeric excess: 94% of anti-
diastereomer determined by HPLC analysis Chiralcel AD-H (i-
PrOH/hexane = 5:95), UV 220 nm, flow rate 1.0 mL/min.
tR = 20.1 min (anti, major) and tR = 22.3 min (anti, minor). 1H
NMR (CDCl3, 300 MHz), d: 7.38–7.34 (m, 1H),7.29–7.27 (m, 2H),
7.21–7.18 (m, 1H), 4.78 (d, J = 9.0 Hz, 1H), 3.99 (br s, 1H), 2.63–
2.50 (m, 2H), 2.49–2.46 (m, 1H), 2.42–2.31 (m, 1H), 1.84–1.78
(m, 1H), 1.70–1.53 (m, 3H), 1.38–1.29 (m, 1H).
4.3.1. 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexanone 6a
Yield: 99%; anti/syn >99:1. Enantiomeric excess: 96% of anti-dia-
stereomer determined by HPLC analysis Chiralcel AD-H (i-PrOH/
hexane = 10:90), UV 254 nm, flow rate 1.0 mL/min. tR = 33.1 min
(anti, major) and. tR = 25.9 min (anti, minor). 1H NMR (CDCl3,
300 MHz), d: 8.19–8.16 (m, 2H), 7.49–7.44 (m, 2H), 4.86 (d,
4.3.8. 2-(Hydroxy(2-chlorophenyl)methyl)cyclohexanone 6h
Yield: 94%; anti/syn >99:1. Enantiomeric excess: 93% of anti-dia-
stereomer determined by HPLC analysis Chiralcel OD-H (i-PrOH/
hexane = 5:95), UV 220 nm, flow rate 1.0 mL/min. tR = 9.4 min
(anti, major) and tR = 11.9 min (anti, minor). 1H NMR (CDCl3,