Enantioselective Synthesis of (+)-α-Conhydrine and (–)-Sedamine
The combined organic layers were concentrated under reduced
pressure, and the crude product (196 mg) was stirred with (Boc)2O
(0.349 mL, 1.5 mmol) and I2 (38 mg, 10 mol-%) for 3 h. This crude
mixture was extracted with EtOAc (3ϫ20 mL) and washed with
water followed by aq. Na2S2O3 to give crude 24, which was purified
by column chromatography by using petroleum ether/EtOAc (9:1)
as eluent to give the pure Boc alcohol 24. Yield: 95% (0.33 g).
[α]2D5 = –19.2 (c = 1, CHCl3) {ref.[9j] [α]2D5 = –18.9 (c = 1, CHCl3,
70 °C under nitrogen for 8 h, then cooled to 0 °C, then the reaction
was carefully quenched by the sequential addition of water
(0.2 mL) and 15% (w/v) aq. NaOH (0.2 mL). The resulting mixture
was filtered through a pad of Celite and anhydrous Na2SO4 to re-
move solids by rinsing with ethyl acetate. The mixture was concen-
trated under reduced pressure, and the resulting oil was purified by
column chromatography to provide (–)-sedamine (2). Yield: 78%
(70 mg). M.p. 58–59 °C (ref.[9l] m.p. 58–60 °C). [α]2D5 = –89.2 (c =
95% ee)}. IR (CHCl ): ν = 3434, 2935, 2864, 1688, 1419, 1391,
0.86, EtOH) {ref.[9l] [α]2D5 = –89.4 (c = 0.9, EtOH)}. IR (CHCl ): ν
˜
˜
3
3
1254, 1164, 1254, 1142, 1052, 711 cm–1. 1H NMR (200 MHz, = 3367, 3060, 2928, 2851, 1450, 1264, 1061, 752, 659 cm–1. 1H
CDCl3): δ = 1.44 (s, 9 H), 1.48–2.09 (m, 8 H), 2.58–2.72 (m, 1 H),
3.30 (br. t, J = 11.6 Hz, 1 H), 3.54–3.66 (m, 1 H), 3.92 (br. d, J =
12.6 Hz, 1 H), 4.37–4.51 (m, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 19.0, 25.3, 28.2, 29.0, 32.1, 39.0, 45.8, 58.3, 79.7,
NMR (200 MHz, CDCl3): δ = 1.30–1.63 (m, 1 H), 1.66–1.80 (m, 6
H), 2.05–2.18 (m, 1 H), 2.50 (s, 3 H), 2.54–2.68 (m, 1 H), 2.98–3.09
(m, 2 H), 4.89 (dd, J = 10.7, 2.6 Hz, 1 H), 5.80 (br. s, 1 H), 7.28–
7.39 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 20.8, 22.2,
155.9 ppm. C12H23NO3 (229.32): calcd. C 62.85, H 10.11, N 6.11; 26.2, 39.3, 39.9, 52.7, 61.4, 73.3, 125.1, 127.1, 128.2, 145.5 ppm.
found C 62.77, H 9.98, N 6.27.
C14H21NO (219.32): calcd. C 76.67, H 9.65, N 6.39; found C 76.59,
H 9.72, N 6.27.
tert-Butyl (S)-2-(Formylmethyl)piperidine-1-carboxylate (7): DMSO
(0.278 mL, 3.92 mmol) was added to a stirred solution of oxalyl
chloride (0.224 mL, 2.6 mmol) in CH2Cl2 (15 mL) at –78 °C. The Acknowledgments
reaction mixture was stirred for 20 min, and then a solution of
T. M. S. thanks the Council of Scientific Industrial Research
alcohol 24 (0.3 g, 1.3 mmol) in CH2Cl2 (5 mL) was added. After
stirring at –78 °C for 1 h, the reaction was quenched by the ad-
dition of Et3N (0.728 mL, 5.22 mmol). The reaction mixture was
then stirred at 25 °C for 30 min, and water (25 mL) was added. The
organic layer was separated, and the aq. phase was extracted with
CH2Cl2 (3ϫ30 mL). The combined organic layers were washed
with water (3ϫ30 mL), dried with anhydrous Na2SO4 and concen-
trated to give the corresponding crude aldehyde, which was purified
by column chromatography on silica gel by using petroleum ether/
EtOAc (7:3) as eluent to give aldehyde 7 as a colourless oil. Yield:
(CSIR), New Delhi, for the award of senior research fellowships.
The authors are also thankful to Dr. B. D. Kulkarni, Head of the
Chemical Engineering & Process-Development Division (CEPD)
for his constant support and encouragement.
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84% (0.250 g). [α]2D5 = –51.1 (c = 0.9, CHCl ). IR (CHCl ): ν =
˜
3
3
2980, 2872, 1741, 1700, 1480, 1411, 1372, 1160, 1055, 872,
770 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.45 (s, 9 H), 1.50–
1.76 (m, 6 H), 2.53–2.58 (m, 1 H), 2.71–2.82 (m, 2 H), 3.98 (br. d,
J = 12.8 Hz, 1 H), 4.83 (br. s, 1 H), 9.73 (t, J = 3.1 Hz, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 18.5, 24.9, 28.0, 28.5, 38.9, 44.2,
45.3, 79.3, 154.1, 199.8 ppm. C12H21NO3 (227.3): calcd. C 63.41,
H 9.31, N 6.16; found C 63.28, H 9.45, N 5.99.
tert-Butyl (S)-2-[(S)-2-Hydroxy-2-phenylethyl]piperidine-1-carbox-
ylate (25): A solution of aldehyde 7 (250 mg, 1.09 mmol) in THF
(5 mL) was added dropwise to a solution of PhMgBr (0.398 g,
2.19 mmol) in THF (20 mL) at – 78 °C under nitrogen. The solu-
tion was warmed up to –20 °C and stirred for 4 h. The reaction
was then quenched by the addition of saturated aq. NH4Cl (5 mL)
and extracted with CH2Cl2 (3ϫ30 mL). The combined organic lay-
ers were washed with brine, dried with anhydrous Na2SO4 and con-
centrated under reduced pressure to give the corresponding dia-
stereomeric mixture (90% yield, 305 mg) of syn and anti alcohols
(dr = 2:1), which was purified by column chromatography by using
petroleum ether/EtOAc (7:3) as eluent to give the major isomer 25.
Yield: 60.6% (185 mg). [α]2D5 = –128.3 (c = 1.5, CHCl3) {ref.[9t]
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[α]2D5 = –127.2 (c = 1, CHCl , 94.2% ee)}. IR (CHCl ): ν = 3410,
˜
3
3
2943, 1685, 1410, 920, 740 cm–1. 1H NMR (200 MHz, CDCl3): δ =
1.49 (s, 9 H), 1.57–1.89 (m, 7 H), 2.12–2.26 (m, 1 H), 2.79 (t, J =
13.5 Hz, 1 H), 3.88–4.02 (m, 2 H), 4.41 (br. s, 1 H), 4.68–4.81 (m,
1 H), 7.21–7.38 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
18.99, 25.3, 28.4, 29.1, 39.2, 40.2, 48.2, 72.3, 79.6, 125.6, 127.1,
128.2, 144.7, 155.3 ppm. C18H27NO3 (305.41): calcd. C 70.79, H
8.91, N 4.59; found C 70.67, H 8.77, N 4.72.
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(–)-Sedamine (2): A solution of carbamate 25 (125 mg, 0.40 mmol)
in THF (2 mL) was added to a solution of LiAlH4 (31 mg,
0.81 mmol) in THF (10 mL). The reaction mixture was heated to
Eur. J. Org. Chem. 2010, 3437–3444
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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