1994 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Majer et al.
temperature overnight. After addition of water (8 mL), the
reaction mixture was washed with EtOAc (5 mL). The aqueous
layer was acidified to pH 1 with 6 M HCl and extracted with
EtOAc (20 mL × 3). The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residual solid
was recrystallized from EtOAc/hexanes to give 0.050 g of 4a
as a white solid (40% yield): mp 88.6-89.6 °C. 1H NMR (THF-
d8) δ 2.08-1.95 (m, 2H), 2.29-2.17 (m, 1H), 2.50-2.46 (m, 2H),
3.48-3.40 (m, 1H); 13C NMR (THF-d8) δ 30.2, 30.3, 39.3, 172.4,
172.9. Anal. (C5H8O4S) C, H, S.
15H); 13C NMR (CDCl3) δ 26.0, 26.1, 26.8, 28.4, 28.5, 31.6, 46.0,
66.5, 104.8, 126.5, 127.8, 129.6, 144.9, 165.4.
2,2-Dim et h yl-5-(5-t r it ylsu lfa n ylp en t yl)[1,3]d ioxa n e-
4,6-d ion e (10c). Compound 10b was prepared as previously
described for the preparation of 10a ,21 except 8c was used in
place of 8a : white solid (74% yield); 1H NMR (CDCl3) δ 1.25-
1.45 (m, 6H), 1.74 (s, 3H), 1.76 (s, 3H), 1.98-2.05 (m, 2H),
2.12-2.18 (m, 2H), 3.44 (t, J ) 5.5 Hz, 2H), 7.17-7.42 (m,
15H); 13C NMR (CDCl3) δ 26.1, 26.3, 26.9, 28.2, 28.4, 28.7, 31.8,
46.0, 66.4, 104.8, 126.5, 127.8, 129.6, 145.0, 165.5.
3-[2,2-Dim et h yl-4,6-d ioxo-5-(3-t r it ylsu lfa n ylp r op yl)-
[1,3]d ioxa n -5-yl]p r op ion ic Acid Meth yl Ester (11a ). A
solution of 10a (4.6 g, 10 mmol), methyl acrylate (4.5 mL, 50
mmol), and sodium acetate (1.64 g, 20 mmol) in tert-butyl
alcohol (15 mL) was stirred at 60 °C overnight. The solvent
was removed under reduced pressure, and the residue was
taken up with EtOAc (50 mL). The solution was washed with
aqueous 5% KHSO4 (50 mL × 3) and brine (50 mL), dried over
MgSO4, and concentrated. The solid residue was recrystallized
from EtOAc/hexanes to provide 4.42 g of 11a as a white solid
(81% yield): 1H NMR (CDCl3) δ 1.23-1.33 (m, 2H), 1.67 (s,
3H), 1.74 (s, 3H), 1.84-1.92 (m, 2H), 2.10-2.16 (m, 2H), 2.21-
2.28 (m, 2H), 2.34-2.40 (m, 2H), 3.65 (s, 3H), 7.17-7.43 (m,
15H); 13C NMR (CDCl3) δ 24.5, 29.4, 29.5, 29.6, 31.4, 32.6, 37.8,
51.9, 52.8, 66.7, 105.6, 126.7, 127.9, 129.5, 144.7, 168.4, 172.0.
3-[2,2-Dim eth yl-4,6-d ioxo-5-(4-tr itylsu lfa n ylbu tyl)[1,3]-
d ioxa n -5-yl]p r op ion ic Acid Meth yl Ester (11b). Compound
11b was prepared as described for the preparation of 11a ,
except 10b was used in place of 10a : white solid (86% yield);
1H NMR (CDCl3) δ 1.16-1.40 (m, 4H), 1.71 (s, 3H), 1.75 (s,
3H), 1.81-1.87 (m, 2H), 2.07-2.15 (m, 2H), 2.26-2.34 (m, 2H),
2.36-2.42 (m, 2H), 3.66 (s, 3H), 7.16-7.44 (m, 15H); 13C NMR
(CDCl3) δ 24.7, 28.4, 29.4, 29.5, 29.6, 31.3, 32.6, 38.3, 51.9,
53.0, 66.5, 105.7, 126.6, 127.8, 129.5, 144.8, 168.6, 172.1.
3-[2,2-Dim et h yl-4,6-d ioxo-5-(5-t r it ylsu lfa n ylp en t yl)-
[1,3]d ioxa n -5-yl]p r op ion ic Acid Meth yl Ester (11c). Com-
pound 11c was prepared as described for the preparation of
11a , except 10c was used in place of 10a : white solid (79%
yield); 1H NMR (CDCl3) δ 1.11-1.38 (m, 6H), 1.69 (s, 3H), 1.76
(s, 3H), 1.88-1.94 (m, 2H), 2.08-2.13 (m, 2H), 2.28-2.34 (m,
3-(2-Oxotetr a h yd r oth iop h en -3-yl)p r op ion ic Acid Eth yl
Ester (7). To a solution of lithium diisopropylamide (2.0 M
solution, 100 mL, 200 mmol) in THF (100 mL) was added
dropwise a solution of γ-thiobutyrolactone 6 (20.0 g, 196 mmol)
in THF (20 mL) at -75 °C, and the resulting mixture was
stirred at -75 °C for 30 min. To the mixture was added
dropwise a solution of ethyl 3-bromopropionate (39.0 g, 216
mmol) in THF (20 mL) at -75 °C. The reaction mixture was
allowed to gradually warm to room temperature overnight. The
mixture was then poured into H2O (200 mL) and extracted
with EtOAc (100 mL × 3). The combined organic layers were
dried over NaSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (10%
EtOAc/hexanes) to give 6.50 g of 7 as a colorless oil (16%
yield): 1H NMR (CDCl3) δ 1.26 (t, J ) 7.3 Hz, 3H), 1.68-1.74
(m, 1H), 1.85-1.98 (m, 1H), 2.07-2.18 (m, 1H), 2.45 (t, J )
7.8 Hz, 2H), 2.43-2.50 (m, 2H), 3.26-3.32 (m, 2H), 4.13 (q, J
) 7.0 Hz, 2H); 13C NMR (CDCl3) δ 14.6, 25.4, 30.6, 32.2, 32.2,
51.1, 60.9, 173.2, 210.1.
2-(2-Mer ca p toeth yl)p en ta n ed ioic Acid (4c). To a solu-
tion of 7 (2.10 g, 10.4 mmol) in THF (15 mL) was added 2 M
NaOH (35 mL), and the resulting mixture was stirred under
an inert atmosphere at room temperature overnight. The
reaction mixture was washed with Et2O (20 mL × 2), acidified
with 2 M HCl to pH 2, and extracted with EtOAc (20 mL ×
3). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give 1.33 g of 4c as a
white solid (66% yield): 1H NMR (CDCl3) δ 1.43 (t, J ) 8.3
Hz, 1H), 1.65-1.75 (m, 1H), 1.85-2.15 (m, 3H), 2.48 (t, J )
7.3 Hz, 2H), 2.40-2.80 (m, 3H), 11.0-11.7 (br, 2H); 13C NMR
2H), 2.38-2.44 (m, 2H), 3.66 (s, 3H), 7.17-7.42 (m, 15H); 13
C
(CDCl3) δ 22.6, 26.8, 32.0, 36.4, 43.6, 179.9, 181.8. Anal. (C7H12
SO4) C, H, S.
-
NMR (CDCl3) δ 25.0, 28.1, 28.7, 29.4, 29.5, 29.7, 31.7, 32.6,
38.6, 51.9, 53.1, 66.4, 105.6, 126.5, 127.8, 129.5, 144.9, 168.7,
172.1.
4-Tr itylsu lfa n ylbu tyr ic Acid (8b). To a solution of tri-
tylmercaptan (15.18 g, 55 mmol) in toluene (50 mL) was added
sodium methoxide (4.37 M solution in methanol, 27.5 mL, 120
mmol). To the mixture was slowly added a solution of 4-bro-
mobutyric acid (10.02 g, 60 mmol) in methanol (22.5 mL) at
5-10 °C. The mixture was allowed to warm to 50 °C and was
stirred for 2 h. The solvent was removed under reduced
pressure, and the residue was taken up with water (200 mL).
The aqueous solution was acidified with 1 M H2SO4 and
extracted with EtOAc (200 mL × 3). The combined extracts
were dried over MgSO4 and concentrated under reduced
pressure. The crude material was recrystallized from EtOAc/
hexanes to afford 15.20 g of 8b as a white solid (76% yield):
1H NMR (CDCl3) δ 1.67 (quint, J ) 7.1 Hz, 2H), 2.22 (t, J )
2-(3-Tr itylsu lfa n ylp r op yl)p en ta n ed ioic Acid (13a ). A
suspension of 11a (5.47 g, 10 mmol) in 1.75 N NaOH (40 mL)
was stirred at 100 °C for 3 h. The resulting homogeneous
solution was cooled to room temperature, acidified to pH 1 by
1 M H2SO4, and extracted with EtOAc. The extract was
washed with brine (100 mL × 3), dried over MgSO4, and
concentrated to give 12a as a crude material (>100% crude
yield). This material was dissolved in DMSO (30 mL), and the
solution was stirred at 130 °C for 3 h. The solvent was removed
under reduced pressure, and the residue was taken up in
EtOAc (50 mL). The organic solution was washed with water
(50 mL × 3) and brine (50 mL), dried over MgSO4, and
concentrated. The residual material was recrystallized from
EtOAc/hexanes to give 4.30 g of 13a as a white solid (96% yield
for two steps): 1H NMR (CD3OD) δ 1.26-1.43 (m, 3H), 1.44-
1.54 (m, 1H), 1.61-1.80 (m, 2H), 2.08-2.32 (m, 5H), 7.16-
7.41 (m, 15H); 13C NMR (CD3OD) δ 27.5, 28.2, 32.5, 32.6, 32.7,
45.5, 67.7, 127.7, 128.8, 130.7, 146.3, 176.7, 178.9. Anal.
(C27H28O4S) C, H, S.
7.1 Hz, 2H), 2.31 (t, J ) 7.1 Hz, 2H), 7.18-7.44 (m, 15H); 13
C
NMR (CDCl3) δ 24.0, 31.5, 33.2, 67.1, 127.0, 128.3, 130.0, 145.2,
178.9.
5-Tr itylsu lfa n ylp en ta n oic Acid (8c). By the same meth-
ods described above and by use of 5-bromovaleric acid,
compound 8c was produced as a white solid (71% yield): mp
124-125 °C; 1H NMR (CDCl3) δ 1.41 (quint, J ) 7.3 Hz, 2H),
1.58 (quint, J ) 7.4 Hz, 2H), 2.16 (t, J ) 7.3 Hz, 2H), 2.20 (t,
J ) 7.3 Hz, 2H), 7.1-7.3 (m, 9H), 7.3-7.5 (m, 6H); 13C NMR
(CDCl3) δ 23.9, 27.9, 31.4, 33.4, 66.52, 126.6, 127.8, 129.6,
144.9, 179.3.
2-(4-Tr itylsu lfa n ylbu tyl)p en ta n ed ioic a cid (13b). Com-
pound 13b was prepared as described for the preparation of
13a , except 11b was used in place of 11a : white solid
1
(quantitative yield); H NMR (CD3OD) δ 1.18-1.48 (m, 6H),
1.66-1.83 (m, 2H), 2.08-2.18 (m, 2H), 2.21-2.32 (m, 3H),
7.15-7.42 (m, 15H); 13C NMR (CD3OD) δ 27.6, 28.4, 29.5, 32.6,
32.7, 32.8, 45.8, 67.7, 127.7, 128.8, 130.8, 146.5, 176.8, 179.3.
2-(5-Tr itylsu lfan ylpen tyl)pen tan edioic Acid (13c). Com-
pound 13c was prepared as described for the preparation of
13a , except 11c was used in place of 11a : white solid
2,2-Dim eth yl-5-(4-tr itylsu lfa n ylbu tyl)[1,3]d ioxa n e-4,6-
d ion e (10b). Compound 10b was prepared as previously
described for the preparation of 10a ,21 except 8b was used in
place of 8a : white solid (77% yield); 1H NMR (CDCl3) δ 1.34-
1.45 (m, 4H), 1.74 (s, 3H), 1.75 (s, 3H), 1.92-2.02 (m, 2H),
2.10-2.19 (m, 2H), 3.41 (t, J ) 5.2 Hz, 1H), 7.15-7.45 (m,
1
(quantitative yield); H NMR (CD3OD) δ 1.08-1.56 (m, 8H),