C. Shen et al. / Tetrahedron: Asymmetry 22 (2011) 708–712
711
13C NMR). Elemental analyses were performed on Carlo-Erba 1106.
Compounds 2 and 3 and amino alcohols 4 and 5 were prepared by
previously described methods.10,13
J = 15.6 Hz), 4.98 (d, 1H, J = 15.6 Hz), 6.72 (d, 1H, J = 7.5 Hz), 7.05
(t, 1H, J = 7.5 Hz), 7.20 (dt, 1H, J = 1.2, 7.5 Hz), 7.26–7.41 (m, 6H);
13C NMR (400 MHz, DMSO-d6): d 207.2, 176.3, 142.4, 135.6,
129.7, 128.3, 123.6, 109.1, 74.1, 49.0, 43.6, 31.6; MS (EI) m/z
296(M++1); the enantiomeric excess of the product was measured
by chiral stationary phase HPLC analysis using a ChiraCel OJ-H col-
umn (80:20 hexanes/i-PrOH at 0.75 mL/min): major enantiomer:
tR = 18.6 min; minor enantiomer: tR = 21.4 min.
4.2. General procedure for the synthesis of carbohydrate-
derived organocatalyst 6
To a suspension of amino alcohols 5 (0.686 g, 2.0 mmol) in
CH2Cl2 (10 ml) was added 1-isothiocyanato-3,5-bis(trifluoro-
methyl)benzene (2.2 mmol), and the reaction mixture was re-
fluxed for 2.5 h to give a clear solution. The reaction mixture was
allowed to cool to room temperature and the solvent was removed
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (5:1 hexane/ethyl acetate) to give the
desired product. White solid, 92% yield, mp: 85–87 °C; 1H NMR
(400 MHz, DMSO-d6): d 7.81 (s, 1H), 7.58 (s, 1H), 7.42 (s, 2H),
7.31–7.24 (m, 9H), 6.80 (d, J = 7.6 Hz, 1H), 5.51 (s, 1H), 5.07 (d,
J = 3.2 Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H),
4.20 (t, J = 4.8 Hz, 1H), 4.08 (t, J = 4.8 Hz, 1H), 3.83 (m, 1H), 3.71
(t, J = 10.4 Hz, 1H), 3.60 (t, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d 178.2, 137.6, 133.2, 131.4, 128.6, 124.5, 123.6,
121.5, 119.0, 109.3, 99.5, 81.5, 79.8, 79.5, 77.2, 77.1, 77.0, 76.4,
75.2, 75.2, 69.5, 69.1, 63.5; Anal. Calcd for C29H26F6N2O5S: C,
55.43; H, 4.16; N, 4.40. Found: C, 55.47; H, 4.11; N, 4.43.
4.3.4. 3-(2-Oxo-2-phenylethyl)-3-hydroxyindolin-2-one 9d8
White solid, 99% yield, racemic, mp: 171–173 °C; 1H NMR
(400 MHz, DMSO-d6):
d 3.57 (d, J = 17.4 Hz, 1H), 4.06 (d,
J = 17.4 Hz, 1H), 6.05 (br s, 1H), 6.78–6.86 (m, 2H), 7.12–7.17 (m,
1H), 7.26 (d, J = 7.5 Hz, 1H), 7.45–7.50 (m, 2H), 7.61 (t, J = 7.8 Hz,
2H), 7.85–7.88 (m, 2H), 10.24 (br s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 196.3, 178.2, 142.5, 136.1, 133.1, 131.5, 128.6,
127.3, 123.2, 120.9, 109.3, 72.9, 45.8; MS (EI) m/z 268 (M++1).
4.3.5. (S)-5-Chloro-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9e8
Pale yellow solid, 95% yield, 72% ee. Mp: 158–159 °C;
½
a 2D5
ꢁ
¼ ꢀ16:3 (c 0.77, MeOH); 1H NMR (400 MHz, DMSO-d6): d
2.09 (s, 3H), 3.20 (d, 1H, J = 12.0 Hz), 3.42 (d, 1H, J = 10.8 Hz),
4.85 (s, 1H), 6.81 (d, 1H, J = 8.0 Hz), 7.33 (s, 1H), 7.41 (d, 1H,
J = 4.4 Hz), 7.51 (d, 1H, J = 2.4 Hz); 13C NMR (100 MHz, DMSO-d6):
d 207.2, 180.6, 143.3, 135.1, 132.9, 128.5, 115.8, 112.2, 75.7, 51.4,
30.9; MS (EI) m/z 240 (M++1). The enantiomeric excess of the prod-
uct was measured by chiral stationary phase HPLC analysis using a
ChiraCel OJ-H column (80:20 hexanes/i-PrOH at 0.75 mL/min): ma-
jor enantiomer: tR = 13.1 min; minor enantiomer: tR = 16.0 min.
4.3. General procedure for the aldol reaction of isatins with
ketones
The organocatalyst 5 (5.9 mg, 0.01 mmol, 10 mol %) and isatin 7
(0.10 mmol) were stirred in CH2Cl2 (2.0 mL) for 15 min at 0 °C. The
corresponding ketone 8 (8.0 mmol for acetone or 3.0 mmol for
other ketones) was added and the mixture was stirred at 0 °C for
the time given in the Tables. The solvent was then removed under
reduced pressure and the mixture was purified by flash column
chromatography on silica gel (1:5 hexane/ethyl acetate) to give
the desired aldol product.
4.3.6. (S)-5-Bromo-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9f8
Pale yellow solid, 82% yield, 75% ee. Mp: 145–147 °C;
½
a 2D5
ꢁ
¼ ꢀ17:6 (c 0.73, MeOH); 1H NMR (400 MHz, DMSO-d6): d
2.02 (s, 3H), 3.07 (d, J = 17.2 Hz, 1H), 3.39 (d, J = 17.2 Hz, 1H),
6.09 (br s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H),
7.43 (s, 1H), 10.36 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): d
205.3, 177.8, 142.0, 134.2, 131.6, 126.7, 113.0, 111.4, 72.6, 50.0,
30.3; MS (EI) m/z 284 (M++1). The enantiomeric excess of the prod-
uct was measured by chiral stationary phase HPLC analysis using a
ChiraCel OJ-H column (70:30 hexanes/i-PrOH at 1.0 mL/min): ma-
jor enantiomer: tR = 8.8 min; minor enantiomer: tR = 11.7 min.
4.3.1. (S)-3-(2-Oxopropyl)-3-hydroxyindolin-2-one 9a5
Pale yellow solid, 99% yield, 67% ee. Mp: 166–168 °C;
½
a 2D5
ꢁ
¼ ꢀ18:4 (c 0.82, MeOH); 1H NMR (400 MHz, DMSO-d6): d
2.00 (s, 3H), 3.01 (d, J = 12.8 Hz, 1H), 3.28 (d, J = 11.2 Hz, 1H),
5.99 (br s, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H),
7.14 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 10.23 (br s, 1H);
13C NMR (100 MHz, DMSO-d6): d 205.6, 178.5, 142.8, 131.4,
128.9, 123.6, 121.5, 109.3, 72.8, 50.2, 30.7; MS (EI) m/z 206
(M++1); the enantiomeric excess of the product was measured by
chiral stationary phase HPLC analysis using a ChiraCel OJ-H column
(80:20 hexanes/i-PrOH at 1.0 mL/min): major enantiomer:
tR = 13.9 min; minor enantiomer: tR = 16.7 min.
4.3.7. (S)-5-Methyl-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9g8
Pale yellow solid, 80% yield, 63% ee. Mp: 161–163 °C;
½
a 2D5
ꢁ
¼ ꢀ11:2 (c 0.52, MeOH); 1H NMR (400 MHz, DMSO-d6): d
2.02 (s, 3H), 2.21 (s, 3H), 2.98 (d, J = 16.0 Hz, 1H), 3.25 (d,
J = 7.2 Hz, 1H), 5.90 (s, 1H), 6.65(d, J = 7.2 Hz, 1H), 6.94 (d,
J = 7.2 Hz, 1H), 7.05 (s, 2H), 10.11 (br s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 205.3, 178.2, 140.3, 132.0, 129.9, 129.2, 124.3,
109.2, 73.3, 50.6, 30.5, 20.8; MS (EI) m/z 220 (M++1). The enantio-
meric excess of the product was measured by chiral stationary
phase HPLC analysis using a ChiraCel AD-H column (80:20 hex-
anes/i-PrOH at 1.0 mL/min): major enantiomer: tR = 10.2 min; min-
or enantiomer: tR = 12.4 min.
4.3.2. (S)-1-Methyl 3-(2-oxopropyl)-3-hydroxyindolin-2-one 9b5
White solid, 97% yield, 65% ee. Mp: 153–155 °C; ½a D25
¼ ꢀ11:4 (c
ꢁ
0.65, MeOH); 1H NMR (400 MHz, DMSO-d6): d 2.14 (s, 3H), 2.99 (d,
1H, J = 17.1 Hz), 3.18 (s, 3H), 3.22 (d, 1H, J = 17.1 Hz), 4.64 (s, 1H),
6.83 (d, 1H, J = 7.5 Hz), 7.05 (d, 1H, J = 7.8 Hz), 7.27–7.37 (m, 2H);
13C NMR (100 MHz, DMSO-d6): d 207.3, 176.5, 143.6, 129.7,
123.7, 108.3, 74.2, 49.0, 31.3, 26.2; MS (EI) m/z 220 (M++1); the
enantiomeric excess of the product was measured by chiral sta-
tionary phase HPLC analysis using a ChiraCel OJ-H column (85:15
hexanes/i-PrOH at 1.0 mL/min): major enantiomer: tR = 13.9 min;
minor enantiomer: tR = 15.6 min.
4.3.8. (S)-(2-Oxocyclohexyl)indolin-3-hydroxyindolin-2-one
9h12
White solid, 99% yield; 63% ee; 81% dr. Mp: 186–188 °C;
½
a 2D5
ꢁ
¼ ꢀ12:3 (c 0.61, MeOH); 1H NMR (400 MHz, DMSO-d6): d
10.11 (s, 1H), 7.22–7.08 (m, 2H), 6.81–6.72 (m, 2H), 5.76 (s, 1H),
3.10 (d, J = 8.0 Hz, 1H), 2.60–2.55 (m, 1H), 2.35–2.50 (m, 1H),
2.35–2.20 (m, 1H), 2.09–1.56 (m, 5H), 1.52–1.35 (m, 1H); 13C
NMR (100 MHz, DMSO-d6): d 209.5, 178.9, 144.3, 132.0, 129.8,
125.6, 121.4, 111.3, 75.4, 58.2, 42.3, 27.6, 25.3; MS (EI) m/z 246
(M++1). The enantiomeric excess of the product was measured by
chiral stationary phase HPLC analysis using a ChiraCel OJ-H column
4.3.3. (S)-1-Benzyl 3-(2-oxopropyl)-3-hydroxyindolin-2-one 9c5
White solid, 95% yield, 60% ee. Mp: 178–179 °C; ½a D25
¼ ꢀ10:6 (c
ꢁ
0.62, MeOH); 1H NMR (400 MHz, DMSO-d6): d 2.18 (s, 3H), 3.11 (d,
1H, J = 17.1 Hz), 3.31 (d, 1H, J = 17.1 Hz), 4.67 (s, 1H), 4.85 (d, 1H,