L. Emmanuvel et al. / Tetrahedron: Asymmetry 20 (2009) 84–88
87
anhydrous Na2SO4. The combined organic layer was concentrated
under reduced pressure to give the crude amino alcohol 10, which
was purified by column chromatography using petroleum ether/
ethyl acetate (1:1) to give amino alcohol 10 as a colourless solid.
Yield: 85% (2.1 g); mp: 112–114 °C (recrystallized from CHCl3);
temperature. After completion of the reaction, it was quenched
with sodium thiosulfate solution and extracted with ethyl ace-
tate, washed with water, brine and dried over anhydrous
Na2SO4. The combined organic layer was concentrated under re-
duced pressure to give the crude halohydrin 12, which was puri-
fied by column chromatography using petroleum ether/ethyl
acetate (4:1) to give 12 as a gum. Yield: 87% (2.2 g); 1H NMR
(200 MHz, CDCl3): d 1.39– 1.44 (d, J = 8.60 Hz, 1H), 1.53–1.72
(m, 3H), 1.82–1.98 (m, 2H), 2.25 (1H), 2.67–2.74 and 2.80–2.93
(t, J = 13 Hz, 1H), 3.33 and 3.4 (s, 1H), 3.52–3.64 (m, 1H), 3.70–
3.90 (m, 1H), 3.99–4.21 (m, 2H), 4.44 and 4.50 (s, 2H), 5.11
and 5.15 (s, 2H), 7.21–7.35 (m, 10H); IR (CHCl3, cmꢁ1): 3456,
2912, 2872, 1728, 1683, 1031, 819.
½
a 2D5
ꢀ
¼ ꢁ46 (c 1, MeOH); 1H NMR (200 MHz, CDCl3): d 1.21–1.35
(m, 1H), 1.45–1.57 (m, 1H), 1.63–1.74 (m, 1H), 1.98–2.14 (m,
2H), 2.11 (br s, 2H), 2.30–2.41 (dt, J = 9.6, 3.1 Hz, 1H), 2.46–2.59
(dt, J = 12.0, 3.8 Hz, 1H), 2.62–2.75 (m, 1H), 2.92–3.02 (m, 1H),
3.21–3.33 (ddd, J = 13.9, 9.68, 4.18 Hz, 1H), 5.10 (t, J = 1.0 Hz, 1H),
5.13–5.24 (m, 1H), 5.71–5.94 (m, 1H); 13C NMR (50 MHz, CDCl3):
d 28.6, 37.5, 40.2, 49.5, 65.5, 74.7, 122.2, 138.9; IR (KBr, cmꢁ1):
3412, 2942, 2893, 1672, 1395. Anal. Calcd for C8H15NO: C, 68.04;
H, 10.71; N, 9.92. Found: C, 68.09; H, 10.65; N, 9.85.
4.11. O-Benzyl-N-benzyloxycarbonyl febrifugine 14
4.8. (2R,3S)-Benzyl 2-allyl-3-hydroxypiperidine-1-carboxylate
To a stirred solution of 12 (668 mg, 1.8 mmol) in dry metha-
nol (10 mL) was added KOH (0.5 g, 3.6 mmol) and 4-hydroxyqui-
nazoline (263 mg, 1.8 mmol) and the mixture was stirred at the
room temperature for 24 h. Next the solvent was removed under
reduced pressure and the residue extracted with ethyl acetate,
washed with brine and dried over anhydrous Na2SO4. The com-
bined organic layer was concentrated under reduced pressure to
give inseparable mixture of 13 as a viscous liquid, which was
subjected to oxidation as described below. To a stirred solution
of 13 in dry CH2Cl2 was added Dess–Martin periodinane
(848 mg, 2 mmol) at room temperature. After the completion
of the reaction, it was quenched with water. The precipitate
formed was filtered through a sintered funnel and the filtrate
was concentrated and subjected to column chromatographic
purification to give the protected febrifugine 14 as a pale yellow
11
To a mixture of amino alcohol 10 (1.9 g, 13.5 mmol) in THF/H2O
(20 mL, 1:1) was added K2CO3 (3.73 g, 27 mmol) followed by ben-
zyl chloroformate (2.754 g, 16.2 mmol) drop-wise at 0 °C. After
stirring for 5 h, the reaction mixture was extracted with ethyl ace-
tate, washed with water, brine and dried over anhydrous Na2SO4.
The combined organic layer was concentrated under reduced pres-
sure to give the crude N-protected amino alcohol 11, which was
purified by column chromatography using petroleum ether/ethyl
acetate (8:2) to give 11 as a viscous brown oil. ½a D25
¼ ꢁ37 (c 1,
ꢀ
CHCl3); 1H NMR (200 MHz, CDCl3): d 1.39–1.50 (m, 1H), 1.65–
2.05 (m, 4H), 2.17–2.46 (m, 2H), 2.85 (dt, J = 10.24, 2.33 Hz, 1H),
3.83 (br s, 1H), 4.03–4.12 (m, 1H), 4.30–4.38 (m, 1H), 4.98–5.02
(m, 2H), 5.13 (s, 2H), 5.59–5.79 (m, 1H), 7.33 (s, 5H); 13C NMR
(50 MHz, CDCl3): d 19.0, 25.8, 33.8, 38.9, 57.1, 66.7, 72.8, 117.3,
127.8, 127.9, 128.5, 134.4, 136.8, 156.7; IR (neat, cmꢁ1): 3412,
2935, 2889, 1723, 1685, 1352, 1163, 1025, 982. Anal. Calcd for
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.98; H, 7.58;
N, 5.11.
oil. Yield 78%; ½a D25
ꢀ
¼ ꢁ25:0 (c 0.5, CHCl3); lit.5h
½
a 2D5
ꢀ
¼ ꢁ22:0 (c
1.0, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.40 (d, J = 10.5 Hz, 1H),
1.60–1.66 (m, 1H), 1.86–1.93 (m, 2H), 2.74–2.95 (m, 3H), 3.50 (s,
1H), 4.05 (br, 1H), 4.50–5.25 (m, 7H), 7.24–7.31 (m, 10H), 7.46–
7.49 (m, 1H), 7.70–7.90 (m, 4H), 8.24–8.26 (m, 1H); 13C NMR
(50 MHz, CDCl3): d 19.3, 24.1, 39.4, 40.7, 50.5, 50.6, 53.8, 67.2,
70.3, 73.5, 121.7, 126.5, 127.2, 127.4, 127.5, 127.6, 127.9,
128.2, 128.4, 134.3, 136.4, 138.2, 146.4, 148.1, 160.8, 200.0; IR
(neat) 2932, 2895, 1730, 1680, 1620, 1352, 1163 cmꢁ1; Anal.
Calcd for C23H27NO3: C, 75.59; H, 7.45; N, 3.83. Found: C,
75.63; H, 7.52; N, 3.92.
4.9. (2R,3S)-Benzyl 2-allyl-3-(benzyloxy)piperidine-1-carboxyl-
ate 3
To a stirred solution of crude amino alcohol 11 (3.5 g) in DMF
(40 mL) was added 60% sodium hydride (550 mg, 16.2 mmol) dis-
persed in mineral oil at 0 °C. After 5 min of stirring, benzyl bromide
(2.6 g, 15 mmol) was added drop-wise via syringe and allowed to
stir for another 4 h. After completion of the reaction as monitored
by TLC, it was quenched with satd NH4Cl solution. It was then ex-
tracted with ethyl acetate (3 ꢂ 200 mL), washed with water, brine
and dried over anhydrous Na2SO4. The combined organic layer was
concentrated under reduced pressure to give crude product 3,
which was purified by column chromatography using petroleum
ether/ethyl acetate (4:1) to afford 3 as colourless liquid. Yield:
4.12. Febrifugine 1
A mixture of 14 (116 mg, 0.30 mmol) and 6 M aqueous HCl
solution was heated at reflux for 4 h. The mixture was poured
into saturated aqueous NaHCO3 solution (50 mL) and extracted
with ethyl acetate. The organic layer was washed with brine,
dried and concentrated. The residue was subjected to column
chromatographic purification (neutral Al2O3; ethyl acetate/petro-
leum ether 2:1) to give 1 as colourless needles. Yield: 63%
84% (4.14 g, two steps);
½
a 2D5
ꢀ
¼ ꢁ37 (c 0.8, CHCl3); lit.5h
(57 mg); mp: 138–140 °C (lit.5m mp 139–140 °C); ½a 2D5
¼ þ25:0
ꢀ
½
a 2D5
ꢀ
¼ ꢁ45 (c 1.55, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.36–
(c 0.1, EtOH) {lit.5j
(200 MHz, CDCl3):
½
a 2D5
ꢀ
¼ þ28 (c 0.5, EtOH)}; 1H NMR
1.43 (m, 1H), 1.61–1.95 (m, 3H), 2.11–2.25 (m, 1H), 2.31–2.46
(m, 1H), 2.82–2.93 (dt, J = 13.4, 2.4 Hz, 1H), 3.44 (br s, 1H), 3.99–
4.17 (m, 1H), 4.4–4.67 (m, 3H), 4.97–5.18 (m, 4H), 5.59–5.73 (m,
1H), 7.21–7.29 (m, 10H); 13C NMR (50 MHz, CDCl3): d 19.7, 24.1,
33.9, 38.8, 52.3, 66.9, 70.0, 73.3, 117.4, 127.4, 127.7, 127.8, 128.3,
128.4, 134.5, 137.0, 138.7, 156.1; IR (neat, cmꢁ1): 2939, 2887,
1727, 1680, 1625, 1352, 1163. Anal. Calcd for C23H27NO3: C,
75.59; H, 7.45; N, 3.83. Found: C, 75.63; H, 7.52; N, 3.92.
d 1.30–1.38 (m, 1H), 1.48–1.57 (m, 1H),
1.72–1.74 (m, 1H), 2.07–2.10 (m, 1H), 2.58 (dt, J = 2.4, 12.2 Hz,
1H), 2.65 (dd, J = 7.3, 15.8 Hz, 1H), 2.88 (dd, J = 4.6, 7.7 Hz, 1H),
2.97 (d, J = 12.2 Hz, 1H), 3.12 (dd, J = 4.8, 15.8 Hz, 1H), 3.29 (m,
1H), 4.83 (d, J = 17.4 Hz, 1H), 4.89 (d, J = 17.4 Hz, 1H), 7.51 (dt,
J = 8.1, 1.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.78 (dt, J = 8.1,
1.2 Hz, 1H), 7.90 (s, 1H), 8.28 (dd, J = 0.9, 7.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3):
121.9, 126.8, 127.4, 127.6, 134.5, 146.4, 148.2, 161.0, 202.7; IR
(KBr, cmꢁ1
2928, 2856, 1722, 1675, 1616. Anal. Calcd for
d 25.7, 35.3, 44.0, 45.9, 54.7, 60.1, 72.2,
4.10. Diastereomers of halohydrin 12
)
C16H19N3O3: C, 63.77; H, 6.36; N, 13.94. Found: C, 63.79; H,
6.39; N, 13.96.
To a stirred solution of 3 (2 g, 5.48 mmol) in CH3CN/H2O (2:1,
20 mL) was added N-bromosuccinimide (1.67 g, 6 mmol) at room