Zhang et al.
Hz), 5.04 (dd, 0.91H, J ) 5.1, 14.9 Hz), 4.83-4.68 (m, 1H),
4.02-3.96 (m, 1H), 3.53-3.45 (m, 1H), 3.27-2.52 (m, 5H),
83.2, 60.4, 49.0, 34.5, 33.4, 25.9, 18.4, -5.6. Anal. Calcd for
C17H27ClN2O4Si: C, 52.77; H, 7.03; N, 7.24. Found: C, 52.39;
H, 7.14; N, 6.93.
2.22-2.03 (m, 1H), 1.97-1.58 (m, 7H). Anal. Calcd for C16H21
-
ClN2O4S: C, 51.54; H, 5.68; N, 7.51; S, 8.60. Found: C, 51.29;
H, 5.82; N, 7.36; S, 8.31.
Rea ction of 11 w ith Con cen tr a ted HCl. A solution of
11 (100 mg, 0.26 mmol) and concentrated HCl (1.0 mL) was
allowed to react at rt for 1 h, diluted with water, and extracted
with EtOAc. The extract was dried and concentrated. The
residue was subjected to chromatography on silica gel with
EtOAc and hexanes (1:2). The major product was lactone 12
(43 mg, 80%): 1H NMR δ 8.22 (d, 1H, J ) 2.6 Hz), 7.56 (dd,
1H, J ) 2.6, 8.2 Hz), 7.29 (d, 1H, J ) 8.2 Hz), 4.34-4.13 (m,
2H), 3.23-3.14 (m, 1H), 2.91-2.78 (m, 2H), 2.35-2.25 (m, 1H),
2.04-1.90 (m, 1H); 13C NMR δ 177.7, 150.2, 149.9, 139.4, 132.6,
124.3, 66.4, 40.5, 32.3, 27.8. Anal. Calcd for C10H10ClNO2: C,
56.75; H, 4.76; N, 6.62. Found: C, 56.90; H, 4.70; N, 6.47.
Rea ction of 11 w ith TBAF . Compound 11 (140 mg, 0.36
mmol) was mixed with a solution of TBAF in THF (1.0 M, 2.0
mL, 2.0 mmol) and stirred at rt for 4 h. The solution was then
diluted with water and extracted with EtOAc. The extract was
dried and concentrated. The residue was subjected to chro-
matography with EtOAc and hexanes (1:2). The major product
was lactone 12 (75 mg, 98%).
4-Meth ylsu lfa n ylbu tyr ic Acid P h en yl Ester (14). To a
stirred solution of 4-methylsulfanylbutyric acid (13) (0.91 g,
6.8 mmol, prepared by reaction of γ-butyrolactone and sodium
thiomethoxide in HMPA13), DCC (1.55 g, 7.5 mmol), and
DMAP (0.17 g, 1.4 mmol) in CH2Cl2 (14 mL) was added a
solution of PhOH (0.77 g, 8.2 mmol) in CH2Cl2 (4.0 mL). The
mixture was stirred overnight at rt, concentrated, dissolved
in EtOAc, and filtered. The filtrate was concentrated and
subjected to silica gel column chromatography with EtOAc and
hexanes (1:10) to give 14 as an oil (1.30 g, 91%): 1H NMR δ
7.42-7.08 (m, 5H), 2.72 (t, 2H, J ) 7.2 Hz), 2.63 (t, 2H, J )
7.2 Hz), 2.14 (t, 3H), 2.06 (quintet, 2H, J ) 7.2 Hz); 13C NMR
δ 171.6, 150.6, 129.3, 125.7, 121.4, 33.4, 32.9, 23.9, 15.3. Anal.
Calcd for C11H14O2S: C, 62.83; H, 6.71. Found: C, 62.96; H,
6.90.
3-(6-Ch lor op yr id in -3-yl)m et h yl-2-n it r om et h ylen et et -
r a h yd r oth iop h en e (2). Compound 7 (0.40 g, 1.1 mmol) was
mixed with concentrated HCl (6.0 mL), kept at rt for 30 min,
and then diluted with water (40 mL). The aqueous solution
was extracted with EtOAc, dried with Na2SO4, and concen-
trated. The residue was subjected to silica gel chromatography
with EtOAc and hexanes (1:1) to give 2 as a pale yellow solid
(0.25 g, 86%), which was identified as the Z-isomer by NOESY
1
experiment: mp 103-104 °C; H NMR δ 8.24 (d, 1H, J ) 2.6
Hz), 7.48 (dd, 1H, J ) 2.6, 8.2 Hz), 7.32 (d, 1H, J ) 8.2 Hz),
7.26 (d, 1H, J ) 1.0 Hz), 3.33-3.25 (m, 1H), 3.21-3.06 (m,
2H), 2.96 (dd, 1H, J ) 6.2, 13.9 Hz), 2.75 (dd, 1H, J ) 8.7,
13.9 Hz), 2.23-2.12 (m, 1H), 2.05-1.95 (m, 1H); 13C NMR δ
167.4, 150.5, 149.9, 139.2, 132.3, 128.4, 124.4, 50.1, 35.8, 33.4,
32.8; EIMS m/z 270 (17, M+). Anal. Calcd for C11H11ClN2O2S:
C, 48.80; H, 4.10; N, 10.35. Found: C, 48.93; H, 4.14; N, 10.15.
4-(ter t-Bu tyld im eth ylsila n yloxy)bu tyr ic Acid P h en yl
Ester (9). To a stirred solution of 4-(tert-butyldimethylsila-
nyloxy)butyric acid (8) (prepared from sodium 4-hydroxybu-
tyrate according to Renton’s method,11,12 5.25 g, 23.6 mmol),
DCC (5.40 g, 26.0 mmol), and DMAP (0.58 g, 4.7 mmol) in
CH2Cl2 (50 mL) was added PhOH (2.70 g, 28.4 mmol). The
mixture was stirred overnight, concentrated, dissolved in
EtOAc, and filtered. The filtrate was concentrated and sub-
jected to silica gel column chromatography with EtOAc and
hexanes (1:30) to give 9 as an oil (5.60 g, 80%): 1H NMR δ
7.42-7.08 (m, 5H), 3.74 (t, 2H, J ) 6.0 Hz), 2.67 (t, 2H, J )
7.2 Hz), 2.01-1.92 (m, 2H), 0.93 (s, 9H), 0.09 (s, 6H); 13C NMR
δ 172.1, 150.7, 129.3, 128.3, 125.6, 121.5, 61.8, 30.7, 27.8, 25.9,
18.3, -5.4. Anal. Calcd for C16H26O3Si: C, 65.26; H, 8.90.
Found: C, 65.05; H, 8.86.
4-(ter t-Bu tyld im eth ylsila n yloxy)-2-(6-ch lor op yr id in -3-
ylm eth yl)bu tyr ic Acid P h en yl Ester (10). To a stirred
solution of LDA (2.0 M, 6.0 mL, 12 mmol) in THF (50 mL)
was added dropwise a solution of 9 (2.94 g, 10 mmol) in THF
(10 mL) at -78 °C, and the mixture was stirred for 30 min at
the same temperature. CIMP (3.04 g, 12 mmol) and HMPA
(2.1 mL, 12 mmol) were added. After the mixture was stirred
at rt overnight, the reaction was quenched with saturated
NH4Cl solution and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Silica
gel column chromatography of the residue with CH2Cl2 and
hexanes (1:1) provided 10 as an oil (1.2 g, 30%): 1H NMR δ
8.31 (d, 1H, J ) 2.6 Hz), 7.57 (dd, 1H, J ) 2.6, 8.2 Hz), 7.38-
7.19 (m, 4H), 6.90 (dd, 2H, J ) 1.0, 8.7 Hz), 3.82-3.73 (m,
2H), 3.16-2.92 (m, 3H), 2.14-2.03 (m, 1H), 1.91-1.80 (m, 1H),
0.91 (s, 9H), 0.07 (s, 6H); 13C NMR δ 173.1, 150.4, 150.1, 149.8,
139.3, 133.4, 129.4, 125.9, 124.0, 121.3, 60.4, 43.6, 34.8, 34.5,
25.9, 18.3, -5.4. Anal. Calcd for C22H30ClNO3Si: C, 62.91; H,
7.20; N, 3.33. Found: C, 63.13; H, 7.31; N, 3.19.
2-(6-Ch lor op yr id in -3-ylm et h yl)-4-m et h ylsu lfa n ylb u -
tyr ic Acid P h en yl Ester (15). To a stirred solution of LDA
(2.0 M, 4.8 mL, 9.6 mmol) in THF (30 mL) was added dropwise
a solution of 14 (1.0 g, 4.8 mmol) in THF (10 mL) at -78 °C,
and the mixture was stirred for 30 min at the same temper-
ature. CIMP (2.42 g, 9.6 mmol) and HMPA (1.7 g, 9.6 mmol)
were added. After the mixture was stirred at rt overnight, the
reaction was quenched with saturated NH4Cl solution and
extracted with EtOAc. The extract was washed with water and
brine, dried, and concentrated. Silica gel column chromatog-
raphy of the residue with EtOAc and hexanes (1:5) provided
15 as an oil (1.2 g, 75%): 1H NMR δ 8.32 (d, 1H, J ) 2.5 Hz),
7.58 (dd, 1H, J ) 2.5, 8.2 Hz), 7.39-7.19 (m, 4H), 6.93-6.89
(m, 2H), 3.11-3.03 (m, 2H), 2.96-2.90 (m, 1H), 2.67-2.62 (m,
2H), 2.24-2.14 (m, 1H), 2.11 (s, 3H), 1.98-1.88 (m, 1H); 13C
NMR δ 172.7, 150.3, 150.0, 139.3, 133.0, 129.4, 128.3, 126.0,
124.0, 121.2, 45.9, 34.5, 31.7, 31.2, 15.4. Anal. Calcd for C17H18
-
ClNO2S: C, 60.80; H, 5.40; N, 4.17. Found: C, 60.62; H, 5.60;
N, 4.23.
5-(ter t-Bu tyld im eth ylsila n yloxy)-3-(6-ch lor op yr id in -3-
ylm eth yl)-1-n itr op en ta n -2-on e (11). To a suspension of
potassium tert-butoxide (0.50 g, 4.8 mmol) in DMSO (4.0 mL)
was added nitromethane (0.26 mL, 4.8 mmol) at <20 °C. The
mixture was stirred for 1 h at the same temperature followed
by dropwise addition of a solution of 10 (0.68 g, 1.6 mmol) in
DMSO (2.0 mL). The reaction mixture was stirred overnight
and then poured into ice-water (10 mL). The solution was then
acidified with concentrated HCl to pH 3-4 and extracted with
EtOAc. The extract was dried and concentrated. Chromatog-
raphy with EtOAc and hexanes (1:3) on a silica gel column
provided 11 as an oil (0.28 g, 44%). NMR indicated 11 contains
∼5% of the enol form: 1H NMR δ 8.21 (d, 1H, J ) 2.6 Hz),
7.45 (dd, 1H, J ) 2.6, 8.2 Hz), 7.28 (d, 1H, J ) 8.2 Hz), 5.43
(d, 1H, J ) 14.9 Hz), 5.11 (d, 1H, J ) 14.9 Hz), 3.72-3.61 (m,
2H), 3.07-2.73 (m, 3H), 2.04-1.73 (m, 2H), 0.88 (s, 9H), 0.06
(s, 6H); 13C NMR δ 198.6, 150.1, 149.9, 139.3, 132.7, 124.3,
3-(6-Ch lor op yr id in -3-ylm eth yl)-5-m eth ylsu lfa n yl-1-n i-
tr op en ta n -2-on e (16). To a suspension of potassium tert-
butoxide (0.56 g, 5.4 mmol) in DMSO (3.0 mL) was added
nitromethane (0.29 mL, 5.4 mmol) at <20 °C. The mixture was
stirred for 1 h at the same temperature followed by dropwise
addition of a solution of 15 (0.60 g, 1.8 mmol) in DMSO (1.0
mL). The reaction mixture was stirred overnight and then
poured into ice-water (10 mL). The solution was acidified with
concentrated HCl to pH 1 and extracted with EtOAc. The
extract was dried and concentrated. Chromatography with
EtOAc and hexanes (1:1) on a silica gel column provided 16
as an oil (0.47 g, 87%). NMR indicated that 16 was a mixture
of tautomers: 1H NMR δ 11.87 (br s, 0.18H), 8.20 (d, 1H, J )
2.1 Hz), 7.45 (dd, 1H, J ) 2.1, 8.2 Hz), 7.29 (d, 1H, J ) 8.2
Hz), 6.63 (s, 0.18H), 5.50 (d, 0.82H, J ) 14.9 Hz), 5.06 (d,
0.82H, J ) 14.9 Hz), 3.02-2.43 (m, 5H), 2.21-2.05 (m, 1H),
880 J . Org. Chem., Vol. 69, No. 3, 2004