3080 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19
Hanessian et al.
2.80-2.67 (m, 2H), 2.65-2.54 (m, 1H), 2.36-2.26 (m, 2H), 1.07
(s, 3H), 0.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.64,
163.02, 140.16, 129.79, 129.64, 128.48, 128.45, 126.43, 114.09,
65.39, 61.32, 55.59, 52.98, 52.55, 40.94, 35.93, 33.98, 30.01,
24.90, 20.31; HRMS calcd for C24H32NO5S2 (MH+) 478.1722,
found 478.1714.
was added a solution of alcohol 13 (43.4 mg, 0.121 mmol) and
benzyl bromide (0.13 mL, 1.0 mmol) in DMF (4 mL). The flask
was allowed to warm to -20 °C over 20 min and was stirred
at - 20 °C for 1 h. The reaction mixture was taken up in Et2
O
(10 mL), washed with H2O (3 × 10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by column chromatography (10-50% EtOAc in hexanes) to
afford ether 16f (13.7 mg, 25%) as a clear, colorless oil: [R]D
+21.3 (c 0.30, CHCl3); TLC Rf ) 0.53 (50% EtOAc in hexanes);
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-(4-m et h oxy-ben zylsu lfa n ylm et h yl)-p yr r olid in e-2-ca r -
boxylic Acid Meth yl Ester (15e). Sulfide 15e (40.2 mg, 55%
from alcohol 13) was prepared according to the general
procedure for preparation of sulfides from mesylate 14. Data
for 15e: [R]D ) +97.6 (c 0.51, CHCl3); TLC Rf ) 0.37 (40%
EtOAc in hexanes); IR (neat) 1748, 1596, 1512 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 7.15 (d, J ) 9.0
Hz, 2H), 6.97 (d, J ) 9.0 Hz, 2H), 6.81 (d, J ) 9.0 Hz, 2H),
3.87 (d, J ) 10.0 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.72 (s,
3H), 3.58-3.53 (m, 2H), 3.26-3.16 (m, 2H), 2.43-2.33 (m, 1H),
2.32-2.14 (m, 2H), 0.98 (s, 3H), 0.50 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 171.43, 161.79, 157.34, 129.98, 129.57, 128.56,
114.06, 113.82, 65.33, 61.39, 55.55, 55.22, 52.51, 40.83, 35.61,
28.14, 24.82, 20.23; HRMS calcd for C24H32NO6S2 (MH+)
494.1671, found 494.1630.
1
IR (neat) 1751, 1596, 1497 cm-1; H NMR (300 MHz, CDCl3)
δ 7.81 (d, J ) 9.0 Hz, 2H), 7.39-7.22 (m, 5H), 6.94 (d, J ) 9.0
Hz, 2H), 4.42 (s, 2H), 4.01 (d, J ) 10.0 Hz, 1H), 3.86 (s, 3H),
3.68 (s, 3H), 3.51 (dd, J ) 10.0, 6.0 Hz, 1H), 3.40 (dd, J ) 9.5,
6.5 Hz, 1H), 3.28-3.20 (m, 2H), 2.40-2.30 (m, 1H), 1.10 (s,
3H), 0.61 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 172.76, 162.96,
137.84, 129.66, 128.30, 127.60, 127.40, 114.04, 73.23, 68.02,
63.80, 61.63, 55.56, 53.20, 52.40, 40.23, 25.48, 20.73; HRMS
calcd for C16H23N2O5S (MH+) 355.1328, found 355.1332.
(2R,3R)-3-Ben zyloxym eth yl-1-(4-m eth oxy-ben zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Hy-
d r oxya m id e (5f). Hydroxamic acid 5f (7.7 mg, 64%) was
prepared from 16f according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5f: [R]D
+49.9 (c 0.39, CHCl3); TLC Rf ) 0.60 (EtOAc); IR (neat) 3269
(2R ,3R )-3-Be n zylsu lfa n ylm e t h yl-1-(4-m e t h oxy-b e n -
zen esu lfon yl)-4,4-dim eth yl-pyr r olidin e-2-car boxylic Acid
Hyd r oxya m id e (5a ). Hydroxamic acid 5a (14.4 mg, 80%) was
prepared from 15a according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5a : [R]D
+151 (c 1.08, CHCl3); TLC Rf ) 0.65 (EtOAc); IR (neat) 3331
(br), 1667, 1595, 1497 cm-1 1H NMR (400 MHz, CD3OD) δ
;
7.82 (d, J ) 9.0 Hz, 2H), 7.34-7.22 (m, 5H), 7.08 (d, J ) 9.0
Hz, 2H), 4.47-4.34 (m, 2H), 3.87 (s, 3H), 3.78 (d, J ) 6.5 Hz,
1H), 3.48-3.33 (m, 2H), 3.19 (d, J ) 10 Hz, 1H), 2.35 (m, 1H),
1.08 (s, 3H), 0.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.91,
143.65, 139.40, 130.98, 130.42, 129.30, 128.64, 128.56, 115.37,
74.10, 68.73, 64.19, 63.16, 56.19, 54.01, 41.14, 25.95, 21.04;
HRMS calcd for C22H29N2O6S (MH+) 449.1746, found 449.1735.
(br), 3202 (br), 1667, 1595, 1496 cm-1 1H NMR (400 MHz,
;
CD3OD) δ 7.80 (d, J ) 9.0 Hz, 2H), 7.31-7.25 (m, 4H), 7.25-
7.17 (m, 1H), 7.06 (d, J ) 9.0 Hz, 2H), 3.87 (s, 3H), 3.72 (d, J
) 8.5 Hz, 1H), 3.65 (s, 2H), 3.28 (d, J ) 10.0 Hz, 1H), 3.21 (d,
J ) 10.0 Hz, 1H), 2.42-2.35 (m, 2H), 2.16-2.06 (m, 1H), 0.97
(s, 3H), 0.45 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 170.78,
164.94, 149.61, 139.31, 130.91, 130.16, 129.47, 128.01, 115.43,
66.14, 62.83, 56.23, 52.51, 41.75, 36.75, 29.53, 25.48, 20.56;
HRMS calcd for C22H29N2O5S2 (MH+) 465.1518, found 465.1534.
(2R,3R)-3-(1-(R,S)-1,2-Dih yd r oxy-eth yl)-1-(4-m eth oxy-
b en zen esu lfon yl)-4,4-d im et h yl-p yr r olid in e-2-ca r b oxyl-
ic Acid Meth yl Ester (17). To a solution of olefin 12 (140.0
mg, 0.396 mmol) and NMO (58.2 mg, 0.496 mmol) in acetone/
H2O (1:1, 5 mL) at room temperature was added OsO4 (4%
aqueous solution, 0.05 mL). The solution was stirred at room
temperature 2 days, extracted with EtOAc (3 × 25 mL) from
H2O (10 mL), dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography
(20-100% EtOAc in hexanes) to afford diol (0.134 g, 87%) as
a clear, colorless oil and as a 1.3:1 mixture of diastereomers:
[R]D ) +60.0 (c 0.57, CHCl3); TLC Rf ) 0.16 (50% EtOAc in
hexanes); IR (neat) 3470 (br), 1740, 1595, 1498 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2 × 0.57H), 7.72 (d,
J ) 9.0 Hz, 2 × 0.43H), 6.97 (d, J ) 9.0 Hz, 2H), 4.27 (d, J )
7.0 Hz, 0.57H), 3.91 (d, J ) 9.0 Hz, 0.43H), 3.84 (s, 3H), 3.78-
3.65 (m, 1H), 3.70 (s, 3 × 0.57H), 3.64 (s, 3 × 0.43H), 3.55-
3.40 (m, 2H), 3.08-2.83 (m, 2H), 2.22 (apparent t, J ) 9.0 Hz,
1 × 0.43H), 2.04 (dd, J ) 7.0, 4.0 Hz, 0.57H), 1.14 (s, 3 ×
0.43H), 1.04 (s, 3 × 0.57H), 0.74 (s, 3 × 0.43H), 0.73 (s, 3 ×
0.57H); 13C NMR (100 MHz, CDCl3) δ 173.90, 173.25, 162.92,
162.86, 130.29, 129.58, 129.28, 129.11, 114.00, 113.96, 71.40,
69.64, 65.37, 64.90, 62.13, 61.76, 61.36, 61.32, 55.47, 54.94,
54.48, 52.50, 41.26, 40.44, 26.38, 25.99, 21.15, 20.94; HRMS
calcd for C17H26NO7S (MH+) 388.1430, found 388.1427.
(2R,3R)-3-((R,S)-1-Hyd r oxy-2-p h en ylsu lfa n yl-eth yl)-1-
(4-m eth oxy-ben zen esu lfon yl)-4,4-d im eth yl-p yr r olid in e-
2-ca r boxylic Acid Meth yl Ester (18). To a solution of diol
17 (44.2 mg, 0.114 mmol) and p-TsCl (23.2 mg, 0.125 mmol)
in CH2Cl2 (2 mL) at 0 °C were added Et3N (16.5 µL, 0.113
mmol) and pyridine (15.5 µL, 0.112 mmol). The solution was
stirred at 0 °C for 3 h, at which time TLC indicated the
complete consumption of starting material. The reaction
mixture was extracted with CH2Cl2 (3 × 10 mL) from H2O (10
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude tosylate was carried on without further purification.
A solution of the crude tosylate and PhSNa (29.7 mg, 0.224
mmol) in dry DMF (2 mL) was stirred at room temperature
for 2 days, taken up in Et2O (5 mL), washed with H2O (3 × 5
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (20-50%
EtOAc in hexanes) to afford sulfide 18 (44.9 mg, 84%) as a
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-ph en eth ylsu lfan ylm eth yl-pyr r olidin e-2-car boxylic Acid
Hyd r oxya m id e (5d ). Hydroxamic acid 5d (14.2 mg, 79%) was
prepared from 15d according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5d : [R]D
+108.4 (c 0.71, CHCl3); TLC Rf ) 0.81 (EtOAc); IR (neat) 3321
(br), 3207 (br), 1667, 1595, 1497 cm-1 1H NMR (400 MHz,
;
CD3OD) δ 7.83 (d, J ) 9.0 Hz, 2H), 7.28-7.10 (m, 5H), 7.09
(d, J ) 9.0 Hz, 2H), 3.88 (s, 3H), 3.73 (d, J ) 8.5 Hz, 1H),
3.30-3.19 (m, 2H), 2.86-2.80 (m, 2H), 2.75-2.66 (m, 2H), 2.54
(dd, J ) 13.0, 6.0 Hz, 1H), 2.30 (dd, J ) 8.0, 6.0 Hz, 1H), 2.21
(dd, J ) 13.0, 8.0 Hz, 1H), 1.07 (s, 3H), 0.44 (s, 3H): 13C NMR
(100 MHz, CD3OD) δ 171.04, 165.12, 142.06, 131.11, 130.64,
129.79, 129.58, 127.43, 115.61, 66.35, 62.97, 56.40, 53.38,
41.93, 37.19, 34.91, 30.87, 25.72, 20.77; HRMS calcd for
C
23H31N2O5S2 (MH+) 479.1674, found 479.1685.
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-3-(4-m eth oxy-
b en zylsu lfa n ylm et h yl)-4,4-d im et h yl-p yr r olid in e-2-ca r -
boxylic Acid Hyd r oxya m id e (5e). Hydroxamic acid 5e (21.1
mg, 52%) was prepared from 15e according to the general
procedure for preparation of hydroxamic acids from esters,
modified as follows: the reaction mixture was stirred at room
temperature overnight. Data for 5e: [R]D +159.0 (c 1.05,
CHCl3); TLC Rf ) 0.69 (EtOAc); IR (neat) 3331 (br), 3197 (br),
1666, 1595, 1511 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.81 (d,
J ) 9.0 Hz, 2H), 7.18 (d, J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz,
2H), 6.82 (d, J ) 9.0 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71
(d, J ) 8.0 Hz, 1H), 3.61 (s, 2H), 3.25-3.17 (m, 2H), 2.40-
2.32 (m, 2H), 2.14-2.04 (m, 1H), 1.01 (s, 3H), 0.38 (s, 3H); 13
C
NMR (100 MHz, CD3OD) δ 170.94, 165.09, 160.34, 131.37,
131.23, 131.07, 130.70, 115.59, 114.99, 66.31, 62.99, 56.39,
55.82, 52.68, 41.89, 36.29, 29.60, 25.69, 20.73; LRMS: 495
(MH+), 434 (M-CO2NH2)+, 373 (M-PMB)+.
(2R,3R)-3-Ben zyloxym eth yl-1-(4-m eth oxy-ben zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Meth -
yl Ester (16f). To NaH (60 mg, 60% dispersion in oil, 0.864
mmol), washed free of oil with hexanes (4 × 3 mL) at -78 °C,