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quenched with deionized water (180 ml). The pH of the Procedure for Michael addition reactions in Table 1
mixture was adjusted to 1 using HCl (1 M) and washed with
Trans-β-nitrostyrene (60 mg, 0.4 mmol), dimethyl malonate
ethyl acetate (2 × 250 ml + 100 ml). The aqueous layer pH was
(158 mg, 1.2 mmol), naphthalene (30 mg) and the catalysts
then adjusted to 8 using ammonium hydroxide and washed
were placed in cylindrical tubes (see Table 1). THF (0.4 ml) was
with dichloromethane (3 × 250 ml). The organic layers were
then added to each tube and the resulting mixture stirred at
−20 °C using a Teflon-coated stir bar. The mixtures were
sampled every 24 h for HPLC analysis at 230 nm. The reaction
solutions were purified using preparative thin layer chromato-
collected and washed with deionized water (2 × 500 ml) before
drying in vacuo. 4.1 g of a dry brown solid was obtained. Iso-
lated yield = 53%.
1H NMR (400 MHz, (CD3)2SO) δ 10.20 (br, 1H), 8.62 (d, J =
graphy to produce a purified product for chiral analysis.
4.3 Hz, 1H), 7.92 (dd, J = 3.4 Hz, 8.9 Hz, 1H), 7.50 (br, 1H),
(−)-Methyl
2
carbomethoxy-4-nitro-3-phenyl-butyrate,
7.39 (s, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 14.5 Hz, 1H),
5.79–6.00 (m, 1H), 5.12 (br, 1H), 4.95 (d, J = 17.0 Hz, 1H), 4.85
(d, J = 10.3 Hz, 1H), 4.33 (dd, J = 6.4 Hz, 11.8 Hz, 2H), 3.16 (br,
1H), 2.99 (br, 1H), 2.73 (br, 2H), 2.60 (br, 1H), 2.11–2.27 (m,
1H), 1.78–2.00 (m, 1H), 1.67 (br, 1H), 1.40–1.56 (m, 2H),
1.03–1.38 (m, 1H); HRMS m/z for (M + 3H+) = 349.2, (M + 2H+)
= 523.8, (M + H+) = 1045.7.
entries in Table 1. This product was obtained as a light yellow
oil after flash chromatography (elution gradient: ethyl acetate/
isohexane = 1/4 by volume). %ee determined by HPLC analysis
[Daicel Chiralcel OD-H, isohexane : IPA, 70 : 30, 0.9 ml min−1
,
column temperature = 24 °C, λ = 220 nm, t (minor) = 11.7 min,
t (major) = 13.1 min].
Entry 1. This product was obtained as a light yellow oil,
19% ee from a reaction catalysed with compound 3 (10 mol%)
at −20 °C for 7 days. Yield not quantified.
Entry 2. This product was obtained as a light yellow oil,
86% ee from a reaction catalysed with compound 4 (10 mol%)
at −20 °C for 1 day. Yield not quantified.
Entry 3. This product was obtained as a light yellow oil, 7%
ee from a reaction catalysed with catalyst 5 (3.3 mol%) at
−20 °C for 3 days. Yield not quantified.
Preparation of 7. To a mixture of quinidine (3.3 g) and
1,3,5-tris(bromomethyl)benzene (1.2 g, 97 wt%), a solvent
mixture of ethanol–DMF–chloroform (30 ml 5 : 6 : 2 by volume)
was added. The mixture was stirred under reflux (100 °C) for
18 h. While the reaction was also performed under reflux in a
solution of just DMF, small scale isolation of 7 was easier and
faster when the solvent mixture including chloroform was
used. The mixture was then cooled to room temperature and
ether added to it until the solution turned colourless. A pre-
cipitate was filtered off and washed with a solvent mixture of
ether–acetone (750 ml 1 : 2 vol/vol). The precipitate was then
dried in vacuo to afford a dry brown powder (2.8 g). Isolated
yield = 63%.
Entry 4. This product was obtained as a light yellow oil,
94% ee from a reaction catalysed with catalyst 6 (10 mol%) at
−20 °C for 3 days. Yield not quantified.
Procedure for Michael addition reactions in Table 2
1H NMR (MHz, (CD3)2SO) δ 8.85 (d, J = 4.6 Hz, 1H), 8.26 (br,
1H), 8.06 (d, J = 9.7 Hz, 1H), 7.80–7.84 (m, 1H), 7.55 (dd, The nitrostyrene (0.4 mmol), dimethyl malonate (158 mg,
J = 2.1 Hz, 9.7 Hz, 1H), 7.45–7.50 (m, 1H), 6.75–6.87 (m, 1H), 1.2 mmol unless otherwise stated), naphthalene (30 mg) and
6.62 (s, 1H), 5.97–6.10 (m, 1H), 5.10–5.19 (m, 2H), 4.81–4.95 catalyst 6 were placed in cylindrical tubes (see Table 2). THF
(m, 1H), 3.69–3.81 (m, 2H), 3.44 (s, 3H), 3.15–3.26 (m, 1H), (0.4 ml) was then added to each tube and the resulting
2.89 (s, 2H), 2.31–2.47 (m, 1H), 2.08 (br, 2H), 1.93 (br, 1H), mixture stirred at −20 °C using a Teflon-coated stir bar. The
1.65–1.80 (m, 2H), 1.10–1.24 (m, 1H); HRMS m/z for mixtures were sampled every 24 h for HPLC analysis at
(M3+) = 363.
230 nm. The reaction solutions were purified using preparative
Preparation of 8. O-Desmethylquinidine (2 g) was mixed thin layer chromatography to produce a purified product for
with deionized water (40 g). Solid NaOH (0.24 g) was added to chiral analysis.
this mixture and stirred at room temperature until a clear
Compound 2, this product was obtained as an off-white
yellow solution was formed. The aqueous solution was washed solid after preparative thin layer chromatography (elution gra-
with dichloromethane (2 × 12 ml). The aqueous phase was dient: ethyl acetate/isohexane = 1/4 by volume, Rf = 0.14). % ee
mixed with isopropanol (50 ml) and dried in vacuo. A dry determined by HPLC analysis [Daicel Chiralcel OD-H, iso-
yellow solid was produced (1.9 g) and mixed with dried DMF hexane:IPA, 85 : 15, 1.0 ml min−1, column temperature = 18 °C,
(10 ml). A solution of 1,3,5-tris(bromomethyl)benzene (0.63 g) λ = 220 nm, t (minor) = 20.0 min, t (major) = 22.4 min].
in dried DMF (10 ml) was slowly added to this mixture using a
Entry 1a. This product was obtained in 62% yield and
syringe. The whole reaction mixture was stirred at room temp- 92% ee from a reaction catalysed with catalyst 6 (3.3 mol%)
erature for 4 days. Ethyl acetate (20 ml) was then added into at −20 °C for 2 days.
the mixture over 5 min using a dropping funnel followed by
Entry 1b. This product was obtained in 75% yield and
aqueous ammonium chloride (70 ml, 14 wt%) also using a 93% ee from a reaction catalysed with catalyst 6 (3.3 mol%)
dropping funnel. The mixture was left to stir for 19 h, after at −20 °C for 1 day.
which the crystals were filtered off and washed with NaOH (2 ×
(−)-Methyl 2 carbomethoxy-4-nitro-3-phenyl-butyrate. This
25 ml, 0.1 M) and deionized water (3 × 25 ml). The residue was product was obtained as a light yellow oil after flash chromato-
then dried in vacuo. 1.2 g of a brown solid produced. Isolated graphy (elution gradient: ethyl acetate/isohexane = 1/4 by
yield = 68%.
volume). % ee determined by HPLC analysis [Daicel Chiralcel
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 663–674 | 671