R. Noël, C. Vanucci-Bacqué, M.-C. Fargeau-Bellassoued, G. Lhommet
FULL PAPER
J = 8 Hz, 1 H), 7.15–7.45 (m, 5 H) ppm. 13C NMR (62.9 MHz, vents evaporated in vacuo. Purification by silica gel column
CDCl3): δ = 19.9, 25.4, 27.2, 45.6, 51.0, 58.2, 65.0, 74.5, 96.1, 127.1, chromatography (AcOEt/cyclohexane, 3:7) afforded pure 14a
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127.6, 127.8, 144.2, 173.2 ppm. HRMS (CI): calcd. for C16H22NO3 (145 mg, 79%) as a colorless oil: H NMR (250 MHz, CDCl3): δ
[M + H]+ 276.1600; found 276.1598.
= 1.07 (d, J = 7.5 Hz, 3 H), 1.30–1.78 (m, 3 H), 1.47 (s, 9 H), 1.87–
2.04 (m, 1 H), 2.70–3.04 (m, 2 H), 3.19 (s, 3 H), 3.76 (s, 3 H), 3.80–
4.10 (m, 1 H), 4.62–4.85 (m, 1 H) ppm. 13C NMR (62.9 MHz,
CDCl3, rotamers): δ = 12.0 and 12.3 ppm, 20.6, 24.4 and 24.6, 28.3,
32.2, 37.2 and 38.5, 42.1 and 42.6, 46.0 and 47.0, 61.4, 79.1, 154.3,
173.8 ppm. To a solution of compound 14a (145 mg, 0.506 mmol)
in THF (3 mL) at 0 °C a solution of magnesium chloride in THF
(3 , 0.51 mL, 1.53 mmol) was added dropwise. The reaction mix-
ture was stirred for 35 min. The solution was cooled to –20 °C and
quenched by addition of 10 % ammonium chloride solution
(10 mL). The reaction mixture was warmed to room temperature,
and the aqueous layer was extracted with CH2Cl2 (3ϫ10 mL). The
combined organic layers were washed with brine (10 mL), dried
with Na2SO4, and concentrated in vacuo. Column chromatography
on silica gel (AcOEt/cyclohexane, 2:8) afforded pure 11a (119 mg,
97%) as a colorless oil.
1-{(3S,5R,6R,8aR,S)-1-(5-Methyl-3-phenylhexahydro-5H-[1,3]ox-
azolo[3,2-a]pyridine-6-yl}ethanone (13a and 13b): The general pro-
cedure was followed for the reduction of compound 5 (300 mg,
1.17 mmol) in AcOMe. Purification of the crude product by silica
gel column chromatography (AcOEt/cyclohexane, 3:7) afforded 13a
and 13b (262 mg, 87%) as an inseparable colorless oily 77:23 mix-
ture of isomers. IR (neat): ν = 1700 cm–1. For major 13a (from a
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mixture): H NMR (250 MHz, CDCl3): δ = 1.04 (d, J = 7.25 Hz,
3 H), 1.51–1.64 (m, 1 H), 1.70–1.93 (m, 3 H), 2.03 (s, 3 H), 2.83–
2.88 (m, 1 H), 3.34–3.40 (m, 1 H), 3.61–3.72 (m, 1 H), 4.27–4.36
(m, 2 H), 5.01 (dd, J = 4 and 10 Hz, 1 H), 7.20–7.45 (m, 5 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 15.9, 18.7, 27.1, 28.7, 47.5, 49.4,
61.7, 73.6, 87.0, 127.6, 127.9, 128.8, 139.7, 209.9 ppm. For minor
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13b (from a mixture): H NMR (250 MHz, CDCl3): δ = 0.76 (d, J
= 7.0 Hz, 3 H), 1.70–1.93 (m, 1 H), 1.98–2.07 (m, 3 H), 2.34 (s, 3
H), 2.45–2.48 (m, 1 H), 2.71–2.77 (m, 1 H), 3.61–3.72 (m, 2 H),
3.81 (dd, J = 3.75 and 8.50 Hz, 1 H), 4.17–4.24 (m, 1 H), 7.20–
7.45 (m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 19.6, 24.7,
27.1, 31.8, 53.6, 58.0, 65.9, 74.5, 96.1, 127.3, 127.5, 128.5, 143.6,
210.7 ppm. HRMS (CI): calcd. for C16H22NO2 [M + H]+ 260.1651;
found 260.1646.
Pentadec-1-en-3-one (23): To a solution of 22[19a,19b] (3.55 mL,
15.7 mmol) in acetone (125 mL) at 0 °C was added Jones reagent
(5.9 mL) over 15 min. After stirring for 30 min at this temperature,
2-propanol (40 mL) and water (100 mL) were successively added.
The reaction mixture was concentrated in vacuo, and the aqueous
layer was extracted with CH2Cl2 (3ϫ40 mL). The combined or-
ganic layers were washed with saturated NaHCO3 solution (40 mL)
and brine (40 mL), dried with Na2SO4, and concentrated in vacuo.
Column chromatography on silica gel (AcOEt/cyclohexane 5:95)
Methyl (3S,5R,6R,8aR)-5,8a-Dimethyl-3-phenylhexahydro-5H-
[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (19a): The general pro-
cedure was followed for the reduction of compound 6 (500 mg,
1.74 mmol) in MeOH. Purification of the crude product by silica
gel column chromatography (AcOEt/cyclohexane, 1:9) afforded 19a
afforded compound 23 (3.32 g, 94%) as a colorless oil. IR (neat):
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ν = 1705, 1685, 1620 cm–1. H NMR (250 MHz, CDCl ): δ = 0.88
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3
(t, J = 6.5 Hz, 3 H), 1.19–1.38 (m, 18 H), 1.56–1.67 (m, 2 H), 2.58
(t, J = 7.25 Hz, 2 H), 5.81 (dd, J = 1.5 and 10.25 Hz, 1 H), 6.16–
6.41 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 22.8,
24.1, 29.4, 29.6, 29.7, 32.0, 39.7, 127.9, 136.7, 201.1 ppm. C15H28O
(224.38): calcd. C 80.29, H 12.58; found C 80.29, H 12.48.
(423 mg, 84%) as a colorless oil. [α]2D0 = +93.7 (c 0.983, CH2Cl2).
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IR (neat), ν = 1730 cm–1. H NMR (250 MHz, CDCl ): δ = 1.07
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(d, J = 7.25 Hz, 3 H), 1.54 (s, 3 H), 1.68–2.05 (m, 4 H), 2.81–2.91
(m, 1 H), 3.26–3.37 (m, 1 H), 3.57 (s, 3 H), 3.62 (t, J = 8 Hz, 1 H),
4.15 (t, J = 7.5 Hz, 1 H), 4.32 (t, J = 7.5 Hz, 1 H), 7.25–7.45 (m,
5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 17.6, 19.5, 27.7,
32.2, 39.2, 49.8, 51.5, 65.7, 72.2, 92.3, 127.5, 127.7, 128.6, 140.9,
174.5 ppm. HRMS (CI): calcd. for C17H24NO3 [M + H]+ 290.1751;
found 290.1753.
3-Acetyloctadecane-2,6-dione (24): A mixture of 23 (1.9 g,
8.46 mmol), acetylacetone (0.87 mL, 8.47 mmol) and Ni(acac)2
(22 mg, 0.086 mmol) in dioxane (17 mL) was heated at 85 °C for
3 d. The reaction mixture was concentrated in vacuo and purified
by column chromatography to afford 24 (2.3 g, 84%) as a white
solid. M.p. 41–42 °C. IR (neat): ν = 1725, 1710 cm–1. In CDCl , 24
1-{(3S,5R,6R,8aR)-5,8a-Dimethyl-3-phenylhexahydro-5H-[1,3]ox-
azolo[3,2-a]pyridine-6-yl)}ethanone (20a): The general procedure was
followed for the reduction of compound 7 (156 mg, 0.575 mmol)
in MeOH. Purification of the crude product by silica gel column
chromatography (AcOEt/cyclohexane, 2:8) afforded 20a (147 mg,
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3
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is partially enolized (40%) H NMR (250 MHz, CDCl3): δ = 0.88
(t, J = 6.5 Hz, 3 H), 1.20–1.30 (m, 18 H), 1.50–1.60 (m, 2 H), 2.03–
2.12 (m, 1.2 H), 2.14 (s, 2.3 H), 2.19 (s, 3.6 H), 2.33–2.45 (m, 3.3
H), 2.50–2.52 (m, 1.6 H), 3.68 (t, J = 6.75 Hz, 0.6 H), 13.25 (s, 0.4
H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 21.6, 22.8, 23.1,
23.9, 29.3, 29.5, 29.6, 29.7, 32.0, 39.6, 43.1, 43.2, 67.1, 109.2, 191.2,
204.3, 210.2, 210.3 ppm. HRMS (CI): calcd. for C20H36O3Na [M
+ Na]+ 347.2556; found 347.2556.
94%) as a white solid. M.p. 60 °C. [α]2D0 = +36.3 (c 1.005, CH2Cl2).
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IR (neat): ν = 1700 cm–1. H NMR (250 MHz, CDCl ): δ = 1.01
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(d, J = 7.5 Hz, 3 H), 1.53 (s, 3 H), 1.65–2.00 (m, 4 H), 2.00 (s, 3
H), 2.89–2.97 (m, 1 H), 3.30–3.41 (m, 1 H), 3.66 (t, J = 8 Hz, 1
H), 4.17 (t, J = 7.5 Hz, 1 H), 4.36 (t, J = 7.75 Hz, 1 H), 7.25–7.45
(m, 5 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 17.5, 18.8, 27.8,
28.5, 32.2, 47.5, 49.6, 65.8, 72.2, 92.5, 127.5, 127.9, 128.7, 140.7,
209.9 ppm. C17H23NO2 (273.37): calcd. C 74.69, H 8.48, N 5.12;
found C 74.65, H 8.42, N 4.91.
1-{(3S,8aR)-8a-Dodecyl-5-methyl-3-phenyl-2,3,8,8a-tetrahydo-7H-
[1,3]oxazolo[3,2-a]pyridin-6-yl}ethanone (21): To a solution of 24
(130 mg, 0.401 mmol) in CH2Cl2 (4 mL) was added (S)-phenylgly-
cinol (61 mg, 0.445 mmol), 4 Å molecular sieves (400 mg), and p-
TsA (8 mg, 0.042 mmol). The reaction mixture was stirred and
heated at reflux for 24 h and then filtered through a Celite pad.
The organic layer was concentrated in vacuo and column
chromatography on silica gel (AcOEt/cyclohexane, 2:8) afforded
pure 21 (69 mg, 40%) as a colorless oil. [α]2D0 = +307 (c 1.000,
Synthesis of 11a from 10a via 14a: To a cooled (–20 °C) solution of
compound 10a (165 mg, 0.641 mmol) and N,O-dimethylhydroxyl-
amine chlorohydrate (97 mg, 0.994 mmol) in dry THF (13 mL) was
added a solution of isopropylmagesium chloride in THF (2 ,
0.96 mL, 1.92 mmol). After stirring for 20 min, a 10 % aqueous
solution of NH4Cl (10 mL) was added at –20 °C. The reaction mix-
ture was warmed to room temperature and the aqueous layer was
extracted with CH2Cl2 (3ϫ10 mL). The combined organic layers
were washed with brine (10 mL), dried with Na2SO4 and the sol-
CH Cl ). IR (neat): ν = 1630, 1520 cm–1 1H NMR (250 MHz,
.
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2
2
CDCl3): δ = 0.87 (t, J = 7.5 Hz, 3 H), 1.20–1.55 (m, 21 H), 1.60–
1.82 (m, 2 H), 2.15 (s, 3 H), 2.19 (s, 3 H), 2.20–2.45 (m, 2 H), 2.58–
2.66 (m, 1 H), 3.85 (dd, J = 7 and 9 Hz, 1 H), 4.39 (dd, J = 7.5
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Eur. J. Org. Chem. 2007, 476–486