L.-J. Gao, X.-Y. Zhao, M. Vandewalle, P. De Clercq
FULL PAPER
1.28 (m, 2 H), 1.40 (m, 1 H), 1.80 (m, 1 H), 3.61 (m, 2 H). Ϫ 13C 1 H), 7.57 (t, J ϭ 7.6 Hz, 2 H), 7.65 (t, J ϭ 7.4 Hz, 1 H), 7.91 (d,
NMR (50 MHz, CDCl3): δ ϭ 12.31, 19.50, 19.92, 20.45, 27.70, J ϭ 7.7 Hz, 2 H). Ϫ MS; m/z (%): 408 (2), [M]ϩ, 383 (5), 365 (8),
48.42, 63.45. Ϫ MS: m/z (%): 116 (3), 98 (14) [Mϩ Ϫ 18], 85 (38),
69 (25), 57 (32), 43 (100).
283 (4), 267 (8), 183 (42), 135 (40), 108 (36), 73 (100). Ϫ
C22H36O3SSi (408.67): calcd. C 64.66, H 8.88; found C 64.58, H
8.96.
(S)-2-Ethyl-3-methylbutanal (6): To a stirred suspension of alcohol
14 (0.116 g, 1.0 mmol), 4-methylmorpholine N-oxide (0.235 g,
Alkene 19: To a solution of sulfone 5 (0.204 g, 0.5 mmol) in dry
tetrahydrofuran (5 mL) at Ϫ78 °C was added a 2 solution of
lithium diisopropylamide (300 µL, 0.6 mmol) in tetrahydrofuran/
hexane. After stirring for 1 h at Ϫ78 °C, aldehyde 6 (0.090 g,
0.8 mmol) was added and the resulting mixture was stirred at this
temperature for a further 2 h. After the addition of 4-(dimethylami-
no)pyridine (50 mg), triethylamine (1.5 mL), and acetic anhydride
(500 µL), the mixture was stirred for a further 1 h at Ϫ78 °C for
1 h and then slowly allowed to warm to room temperature. The
reaction was then quenched with saturated ammonium chloride so-
lution (5 mL) and the suspension obtained was extracted with di-
ethyl ether. The organic phase was washed with brine and dried
with magnesium sulfate. After filtration and concentration of the
filtrate in vacuo, the yellow oily residue was passed through a short
column of silica gel (ethyl acetate/isooctane, 1:4) to afford a crude
solid (0.290 g). This was immediately dissolved in methanol (5 mL)
and the resulting solution was added to a stirred mixture of 3%
sodium amalgam (4.0 g, 5.2 mmol) and disodium phosphate (1.0 g)
in dry tetrahydrofuran (10 mL) at Ϫ78 °C. The reaction mixture
was stirred at Ϫ78 °C for 1 h and then slowly allowed to warm to
room temperature. After the addition of a 1 solution of tetrabu-
tylammonium fluoride in tetrahydrofuran (5 mL, 5 mmol), the re-
sulting mixture was stirred at room temperature for 12 h. After
quenching with water (20 mL), the suspension obtained was ex-
tracted with diethyl ether. The organic phase was washed with brine
and dried with magnesium sulfate. After filtration and concentra-
tion of the filtrate in vacuo, the residue was purified by flash chro-
matography (isooctane/acetone, 20:1) and HPLC (pentane/acetone,
20:1) to afford alkene 19 (0.098 g, 67% yield) as a colorless oil. Ϫ
[α]2D0 ϭ ϩ27 (c ϭ 0.437, CHCl3). Ϫ Rf ϭ 0.42 (isooctane/ethyl acet-
ate, 5:1). Ϫ IR (film): ν˜ ϭ 3420, 2954, 2869, 1458, 1367, 1167, 1065,
990, 972, 943 cmϪ1. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ
0.86Ϫ0.78 (m, 9 H), 0.948 (s, 3 H), 0.996 (d, J ϭ 6.6 Hz, 3 H), 4.08
(br. s, 1 H), 5.02 (ABd, J ϭ 15.2, 8.6 Hz, 1 H), 5.14 (ABd, J ϭ
15.2, 8.7 Hz, 1 H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 12.4, 13.8,
17.5, 19.1, 21.2, 21.2, 22.7, 25.5, 28.1, 32.0, 33.7, 40.2, 40.4, 41.8,
51.4, 52.8, 56.5, 69.6, 129.5, 138.2. Ϫ MS; m/z (%): 292 (3) [Mϩ],
274 (2), 231 (12), 188 (5), 162 (12), 135 (44), 93 (37), 81 (62), 55
(100).
˚
2.0 mmol), and 4 A molecular sieves (powdered, 0.500 g) in dichlo-
romethane (2 mL), tetrapropylammonium perruthenate (0.020 g,
0.05 mmol) was added in a single portion at room temperature.
After stirring for 1 h, the mixture was passed through a short col-
umn of silica gel eluting with dichloromethane. After concentration
by careful distillation, HPLC (2% acetone in pentane) afforded 6
(0.108 g, 95%) as a colorless liquid. Ϫ Rf ϭ 0.42 (isooctane/ethyl
acetate, 3:2). Ϫ [α]2D0 ϭ ϩ32 (c ϭ 0.322, CHCl3); ref.[13] [α]2D0
ϭ
ϩ37.0. Ϫ IR (film): ν˜ ϭ 2964, 2877, 2706, 1728, 1463, 1388, 1371,
1179 cmϪ1. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 0.9 (br., 9 H),
1.28 (m, 2 H), 1.64 (s, 1 H), 1.97 (m, 1 H), 9.62 (d, J ϭ 3.4 Hz,
1 H). Ϫ MS: m/z (%) ϭ 114 (5) [M]ϩ, 85 (15), 72 (34), 57 (44),
43 (100).
Sulfide 17: A suspension of tosylate 16 (1.0 g, 2.73 mmol), thi-
ophenol (560 µL, 5.46 mmol), and anhydrous potassium carbonate
(1.13 g, 8.19 mmol) in dry dimethyl sulfoxide (25 mL) was stirred
under argon at 30 °C for 3 h. After quenching by pouring into
water, the mixture was extracted with diethyl ether and the organic
phase was washed with brine and dried over magnesium sulfate.
After filtration and concentration, the residue was purified by flash
chromatography on silica gel (isooctane/acetone, 4:1) to afford the
sulfide 17 (0.755 g, 91%) as a colorless oil. Rf ϭ 0.56 (isooctane/
acetone, 3:2). Ϫ IR (film): ν˜ ϭ 3431, 3057, 1584, 1480 cmϪ1. Ϫ 1H
NMR (200 MHz, CDCl3): δ ϭ 0.97 (s, 3 H), 1.15 (d, J ϭ 6.5 Hz,
3 H), 2.70 (dd, J ϭ 12.3, 8.6 Hz, 1 H), 3.18 (dd, J ϭ 12.3, 2.8 Hz,
1 H), 4.13 (br. s, 1 H), 7.10Ϫ7.40 (m, 5 H). Ϫ MS; m/z (%): 304
(75) [M]ϩ, 286 (1), 177 (10), 152 (28), 123 (100).
Sulfone 18: To a solution of sulfide 17 (0.690 g, 2.27 mmol) in dry
dichloromethane (100 mL), a solution of m-chloroperbenzoic acid
(1.350 g, 5.50 mmol) in dry dichloromethane (10 mL) was added
dropwise at room temperature. After stirring for 3 h under argon,
the mixture was quenched with saturated sodium hydrogen carbon-
ate solution. After extraction with diethyl ether, the organic phase
was washed with 10% aqueous sodium sulfite solution and brine,
and dried with magnesium sulfate. After filtration and concentra-
tion of the filtrate in vacuo, the residue was purified by flash chro-
matography (isooctane/acetone, 7:3) to afford sulfone 18 (0.752 g,
99%) as a white solid. Rf ϭ 0.35 (isooctane/acetone, 3:2). Ϫ IR
Alcohol 21: A mixture of alkene 19 (0.065 g, 0.22 mmol) and plat-
inum(IV) oxide hydrate (0.050 g) in ethyl acetate (25 mL) was hy-
drogenated at room temperature for 3 h. After filtration through a
short column of silica gel, HPLC (acetone/pentane, 1:40) afforded
alcohol 20 (0.065 g, 99% yield) as a colorless oil. Rf ϭ 0.42 (isooc-
tane/ethyl acetate, 5:1). Ϫ [α]2D0 ϭ ϩ45 (c ϭ 0.663, CHCl3). Ϫ IR
(film): ν˜ ϭ 3422, 2956, 2871, 1458, 1366, 990 cmϪ1. Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 0.87Ϫ0.80 (m, 9 H), 0.898 (d, J ϭ 6.5 Hz,
3 H), 0.93 (s, 3 H), 4.07 (d, J ϭ 2.2 Hz, 1 H). Ϫ 13C NMR
(50 MHz, CDCl3): δ ϭ 12.2, 13.7, 17.6, 18.8, 19.2, 20.0, 22.7, 23.2,
26.2, 27.3, 29.2, 33.7, 33.9, 35.8, 40.5, 42.0, 45.9, 52.7, 56.7, 69.6.
Ϫ MS; m/z (%): 294 (3) [Mϩ], 278 (1), 233 (1), 180 (2), 163 (4), 135
(10), 125 (12), 111 (100), 97 (20), 69 (19), 55 (36), 43 (36). Ϫ
C20H38O (294.52): calcd. C 81.56, H 13.00; found C 81.53, H 13.07.
1
(KBr): ν˜ ϭ 3536, 3063, 1303, 1145 cmϪ1. Ϫ H NMR (500 MHz,
CDCl3): δ ϭ 0.89 (s, 3 H), 1.17 (d, J ϭ 6.5 Hz, 3 H), 2.84 (dd, J ϭ
14.2, 5.6 Hz, 1 H), 3.14 (dd, J ϭ 14.2, 1.3 Hz, 1 H), 4.05 (br. s, 1
H), 7.93Ϫ7.54 (m, 5 H). Ϫ MS; m/z (%): 321 (5), 177 (9), 135 (24),
77 (100). Ϫ C19H28O3S (336.44): calcd. C 67.83, H 8.39; found C
67.67, H 8.59.
Hydroxy-Protected Sulfone 5: A solution of sulfone 18 (0.703 g,
2.09 mmol) and N-trimethylsilylimidazole (766 µL, 5.23 mmol) in
dry dichloromethane (5 mL) was stirred at room temperature under
argon for 2 h. Subsequent flash chromatography on silica gel (di-
ethyl ether/pentane, 3:7) afforded sulfone 5 (0.821 g, 96% yield) as
white crystals; m.p. 65Ϫ66 °C. Ϫ [α]2D0 ϭ ϩ59 (c ϭ 0.696, CHCl3).
Ϫ Rf ϭ 0.40 (diethyl ether/pentane, 3:7). Ϫ IR (KBr): ν˜ ϭ 2957,
2928, 2864, 1449, 1304, 1250, 1150, 1086, 1033, 840, 743, 723, 688 Ketone 8: To a suspension of alcohol 20 (0.060 g, 0.2 mmol), 4-
1
cmϪ1. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.03 (s, 9 H), 0.83 (s,
methylmorpholine N-oxide (0.050 g, 0.4 mmol), and 4 A molecular
˚
3 H), 1.16 (d, J ϭ 6.5 Hz, 3 H), 1.90 (m, 1 H), 2.03 (m, 1 H), 2.82
sieves (powdered, 0.1 g) in dichloromethane (2 mL) at room tem-
(dd, J ϭ 14.2, 9.8 Hz, 1 H), 3.15 (d, J ϭ 14.2 Hz, 1 H), 3.95 (br. s, perature, tetrapropylammonium perruthenate (5 mg) was added in
2758 Eur. J. Org. Chem. 2000, 2755Ϫ2759