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E. J. Kim, S. Y. Ko / Bioorg. Med. Chem. 13 (2005) 4103–4112
drying (Na2SO4) and concentration, the crude product
was purified on a silica column (hexane–EtOAc 2:1, then
1:3) to afford the diastereomeric mixture 7a and 7b
(7a:b = 1:2.7, 16.1 g, 78%).
Compound 9a: 1H NMR (CDCl3): d 2.42–2.57 (m, 1H),
3.28 (d, J = 8.3 Hz, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 3.64–
4.50 (m, 5H), 5.50 (s, 1H), 6.0 (s, 1H), 6.39 (s, 1H), 6.86–
6.91 (d, 2H), 7.37–7.41 (d, 2H). MS: 309 ([M+H]+).
Compound 7a: 1H NMR (CDCl3): d 2.33–2.38 (m, 1H),
3.53 (br, 1H), 3.65–3.74 (m, 2H), 3.69 (s, 3H), 4.02–4.19
(m, 4H), 5.47 (s, 1H), 6.87–6.90 (d, 2H), 7.37–7.43 (d,
2H). MS: 225 ([M+H]+).
Compound 9b: 1H NMR (CDCl3): d 2.42–2.57 (m, 1H),
2.71 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 3.64–
4.50 (m, 5H), 5.35 (s, 1H), 5.80 (s, 1H), 6.31 (s, 1H),
6.86–6.91 (d, 2H), 7.37–7.41 (d, 2H). MS: 309 ([M+H]+).
Compound 7b: 1H NMR (CDCl3): d 2.33–2.38 (m, 1H),
3.47 (br, 1H), 3.49–3.53 (m, 2H), 3.80 (s, 3H), 4.05–4.31
(m, 4H), 5.37 (s, 1H), 6.87–6.90 (d, 2H), 7.37–7.43 (d,
2H). MS: 225 ([M+H]+).
4.5. Deprotection/lactonization of 9 to give 4-hydroxy-5-
hydroxymethyl-3-methylene-tetrahydro-pyran-2-one (11)
Compound 9 (3.5 g, 11.0 mmol, diastereomeric mixture)
was dissolved in 0.01 N H2SO4 solution. The mixture
was stirred at rt, overnight, then was extracted with
EtOAc. Following drying (Na2SO4) and concentration,
the crude product was purified on a silica column
(EtOAc) to afford 10 and 11 (10:11 = 1:2). This mixture
of 10 and 11 was dissolved in THF (50 mL). Bu4NF
(8 mL of 1.0 M solution in THF) was added, and the
mixture was stirred at rt for 2 h, then diluted with
EtOAc and washed with 10% citric acid and with brine.
Following drying (Na2SO4) and concentration, the
crude product was purified on a silica column (EtOAc)
to afford the lactone 11a and 11b as a mixture of diaste-
reomers (11a:b = 1.5:1, 1.25 g, 72%).
4.3. Oxidation of 7 to give 2-(4-methoxyphenyl)-
[1,3]dioxane-5-carbaldehyde (8)
Anhydrous dichloromethane (30 mL) was placed in a
dry three-neck flask under N2. Oxalyl chloride
(6.4 mL, 76.2 mmol) was added and the solution was
cooled to ꢀ80 °C. DMSO (16 mL, 228.6 mmol) was
added dropwise and the mixture was stirred for
20 min. A solution of 7 (11.4 g, 50.8 mmol, diastereo-
meric mixture) in dry dichloromethane (70 mL) was
added and the mixture was stirred for 30 min, maintain-
ing ꢀ80 °C. Triethylamine (35 mL, 254 mmol) was then
added, and the mixture was warmed to rt, where it was
stirred for 12 h. The mixture was washed with water,
then with brine. Following drying (Na2SO4) and concen-
tration, the crude product was purified on a silica col-
umn (hexane–EtOAc 1:2) to afford the diastereomeric
mixture 8a and 8b (8a:b = 1:0.3, 8.94 g, 86%).
Compound 11a: 1H NMR (CDCl3): d 2.18–2.35 (m, 1H),
2.97 (br, 1H), 3.75–3.91 (m, 2H), 4.11–4.19 (m, 1H), 4.46
(dd, J = 4.3, 11.6 Hz, 1H), 4.53–4.57 (m, 1H), 6.09 (s, 1H),
6.63 (s, 1H). MS: 159 ([M+H]+).
Compound 11b: 1H NMR (CDCl3): d 2.33–2.38 (m,
1H), 3.04 (br, 1H), 3.75–3.91 (m, 2H), 4.34 (dd,
J = 4.4, 11.3 Hz, 1H), 4.59–4.67 (m, 1H), 4.79 (s, 1H),
5.94 (s, 1H), 6.57 (s, 1H). MS: 159 ([M+H]+).
1
Compound 8a: H NMR (CDCl3): d 3.79 (s, 3H), 4.21
(dd, J = 0.9 Hz, 12.2 Hz, 2H), 4.71 (d, J = 12.1 Hz,
2H), 5.50 (s, 1H), 6.84–6.92 (d, 2H), 7.33–7.41 (d, 2H),
10.04 (s, 1H). MS: 223 ([M+H]+).
4.6. Silylation of 11 to give 5-(tert-butyldiphenylsilanyl-
oxymethyl)-4-hydroxy-3-methylene-tetrahydro-pyran-2-
one (12)
Compound 8b: 1H NMR (CDCl3): d 3.24–3.17 (m, 1H),
3.79 (s, 3H), 3.96 (dd, J = 12.1, 11.5 Hz, 2H), 4.51 (dd,
J = 4.6, 11.5 Hz, 2H), 5.38 (s, 1H), 6.84–6.91 (d, 2H),
7.33–7.42 (d, 2H), 9.67 (s, 1H). MS: 223 ([M+H]+).
DMAP (43 mg, 0.35 mmol) and triethylamine (1.33 mL,
9.57 mmol) were dissolved in anhydrous dichlorometh-
ane (15 mL) under N2. A solution of 11 (1.38 g,
8.7 mmol, mixture of diastereomers) in dry dichloro-
methane (25 mL) was added and TBDPS–Cl (2.5 mL,
9.57 mmol) was added dropwise. The mixture was stir-
red at rt for 4 days, then washed with satd NH4Cl and
with brine. Following drying (Na2SO4) and concentra-
tion, the crude product was purified on a silica column
(hexane–EtOAc 2:1, then 1:2) to afford the diastereo-
meric mixture 12a and 12b (12a:b = 1:2, 2.17 g, 65%).
4.4. Baylis–Hillman reaction of 8 to give 2-{hydroxy-[2-
(4-methoxyphenyl)-[1,3]dioxan-5-yl]-methyl}-acrylic acid
methyl ester (9)
Compound 8 (8.5 g, 38.5 mmol, diastereomeric mixture)
was placed in a flask. Methyl acrylate (7 mL, 77 mmol),
DABCO (4.3 g, 38.5 mmol), La(OTf)3 (1.1 g, 1.9 mmol),
and triethanolamine (2.5 mL, 19.3 mmol) were added
successively. A minimum amount of ionic liquid
[bmim][PF6] (0.1 mL) was added to keep the mixture
homogeneous. An equivalent of methyl acrylate
(3.5 mL) was added at every 24 h interval for 5 days.
The mixture was diluted with EtOAc and washed with
water, then with brine. Following drying (Na2SO4)
and concentration, the crude product was purified on
a silica column (hexane–EtOAc 2:1, then 1:1, then 1:3)
to afford the desired product as a mixture of diastereo-
mers 9a and 9b (9a:b = 1:4, 8.6 g, 60%).
Compound 12a: 1H NMR (CDCl3): d 1.07 (s, 9H), 2.12–
2.18 (m, 1H), 2.47 (d, J = 4.6 Hz, 1H), 3.77–3.86 (m,
2H), 4.11–4.15 (m, 1H), 4.38 (dd, J = 4.3, 10.0 Hz,
1H), 4.48–4.56 (m, 1H), 6.04 (s, 1H), 6.61 (s, 1H),
7.38–7.49 (m, 6H), 7.62–7.66 (m, 4H). MS: 396
([MꢀH]+).
Compound 12b: 1H NMR (CDCl3): d 1.07 (s, 9H), 2.33–
2.40 (m, 1H), 3.06 (d, J = 3.6 Hz, 1H), 3.77–3.86 (m,