for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.46; H,
7.44; N, 9.48.
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was adsorbed on silica and filtered through silica
gel with 80% EtOAc/Hexanes (500 mL, first fraction) and 2% Et3N/
EtOAc (800 mL, second fraction). The second fraction filtrate was
concentrated under reduced pressure to give 2.34 g (89%) of
compound 17 as a white foamy solid. 1H NMR (400 MHz, CDCl3)
δ 8.07-8.04 (m, 2H), 7.61-7.45 (m, 5H), 7.38-7.23 (m, 5H),
6.50-6.47 (m, 2H), 5.90 (br t, 1H, J ) 5.6 Hz), 5.46 (br s, 1H),
5.43-5.38 (m, 1H), 4.33 (dd, 1H, J ) 10.8, 3.7 Hz), 3.35 (qd, 2H,
J ) 7.1, 1.3 Hz), 3.07 (dd, 1H, J ) 10.8, 6.2 Hz), 2.96-2.88 (m,
2H), 2.81-2.78 (m, 1H), 2.61 (dd, 1H, J ) 12.2, 4.4 Hz), 2.57-
2.52 (m, 1H), 2.36 (m, 1H), 2.06-1.99 (m, 1H), 1.57 (m, 2H),
0.93 (t, 3H, J ) 7.5 Hz). 13C NMR (101 MHz, CDCl3) δ 167.6
(C), 166.6 (C), 150.7 (C), 142.1 (C), 133.4 (CH), 130.4 (C), 129.8
(CH), 129.0 (CH), 128.7 (CH), 128.5 (CH), 127.7 (CH), 126.5 (CH),
123.6 (C), 113.4 (CH), 74.9 (CH), 63.0 (CH2), 60.1 (CH2), 57.0
(CH), 52.5 (CH2), 41.8 (CH2), 32.2 (CH2), 23.3 (CH2), 11.7 (CH3).
Anal. Calcd for C29H33N3O3: C, 73.86; H, 7.05; N, 8.91. Found:
C, 73.79; H, 7.15; N, 8.86.
Benzoic Acid 1-{2-[Methyl-(4-propylcarbamoyl-phenyl)-
amino]-2-phenyl-ethyl}-pyrrolidin-3-yl Ester (9). Sodium boro-
hydride (80 mg, 2.12 mmol) and trifluoroacetic acid (2.65 mL) were
stirred at room temperature for 20 min. The solution was cooled to
0 °C before addition of DCM (2.65 mL), compound 17 (500 mg,
1.06 mmol), and formaldehyde (37 wt % in H2O, 158 µL, 2.12
mmol). The mixture was stirred at 0 °C for 90 min, warmed to
room temperature, basified with NaOH (1 M), and stirred vigorously
for 15 min. Layers were separated. The aqueous layer was extracted
repeatedly with DCM. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography on silica gel eluting with 60% EtOAc/2% Et3N/hexanes
to yield 443 mg (86%) of 9 (CJ-18,027) as a white foamy solid.
1H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 2H), 7.66-7.62 (m,
2H), 7.58-7.53 (m, 1H), 7.45-7.41 (m, 2H), 7.34-7.25 (m, 5H),
6.83-6.79 (m, 2H), 5.95 (br t, 1H), 5.36-5.32 (m, 1H), 5.17-
5.14 (m, 1H), 3.41-3.36 (m, 2H), 3.11-3.08 (m, 2H), 2.96 (dd,
1H, J ) 10.6, 6.0 Hz), 2.89-2.84 (m, 5H), 2.31-2.23 (m, 1H),
1.96-1.89 (m, 1H), 1.61 (q, 2H, J ) 7.5 Hz), 0.96 (t, 3H, J ) 7.5
Hz). 13C NMR (101 MHz, CDCl3) δ 167.6 (C), 166.6 (C), 152.8
(C), 142.2 (C), 133.2 (CH), 130.5 (C), 129.8 (CH), 128.8 (CH),
128.7 (CH), 128.6 (CH), 127.6 (CH), 127.2 (CH), 122.4 (C), 112.0
(CH), 74.9 (CH), 60.6 (CH), 60.4 (CH2), 57.6 (CH), 53.1 (CH2),
41.8 (CH2), 32.6 (CH3), 32.2 (CH2), 23.3 (CH2), 11.8 (CH3). Anal.
Calcd for C30H35N3O3: C, 74.20; H, 7.26; N, 8.65. Found: C, 74.33;
H, 7.31; N, 8.59.
4-(2-Oxo-4-phenyl-[1,2,3]oxathiazolidin-3-yl)-N-propyl-ben-
zamide (15). Thionyl chloride (200 µL, 2.75 mmol) and anhydrous
pyridine (3.4 mL, 42.04 mmol) were added to dichloromethane (3.7
mL) at 0 °C. A suspension of aminol 14 (500 mg, 1.68 mmol) in
DCM (24 mL) was added dropwise. The funnel was rinsed with
dichloromethane (12 mL), and the resulting mixture was warmed
slowly to room temperature. After stirring for 1 h 15 min, water
and MTBE were added. Layers were separated. The aqueous layer
was extracted with MTBE. The combined organic layers were
washed with brine, dried over K2CO3, filtered, and concentrated to
1
give 575 mg (99%) of compound 15 as a light yellow solid. H
NMR (400 MHz, CDCl3) δ 7.63-7.60 (m, 2H), 7.37-7.29 (m,
3H), 7.26-7.22 (m, 2H), 7.01-6.98 (m, 2H), 6.07 (br t, 1H), 5.36
(dd, 1H, J ) 8.3, 6.6 Hz), 5.29 (dd, 1H, J ) 3.3, 6.6 Hz), 4.52 (dd,
1H, J ) 8.3, 3.3 Hz), 3.35 (m, 2H), 1.58 (m, 2H), 0.93 (t, 3H, J )
7.5 Hz). 13C NMR (101 MHz, CDCl3) δ 167.0 (C), 141.8 (C), 137.1
(C), 129.5 (CH), 129.1 (C), 128.9 (CH), 128.8 (CH), 126.5 (CH),
117.8 (CH), 78.1 (CH2), 61.3 (CH), 41.9 (CH2), 23.1 (CH2), 11.7
(CH3). Anal. Calcd for C18H20N2O3S: C, 62.77; H, 5.85; N, 8.13;
S, 9.31. Found: C, 62.72; H, 5.82; N, 8.03; S, 9.25.
4-(2,2-Dioxo-4-phenyl-[1,2,3]oxathiazolidin-3-yl)-N-propyl-
benzamide (16). Ruthenium(III) chloride hydrate (420 mg, 2.03
mmol) was added to a solution of compound 15 (10.0 g, 29.04
mmol) in dichloromethane (58 mL) and acetonitrile (58 mL) at 0
°C. The mixture was stirred for 10 min before addition of sodium
periodate (9.94 g, 46.46 mmol) and a pH 7 buffer solution (58 mL).
The mixture was stirred for 20 min, warmed to room temperature,
and filtered through a pad of Celite. The residual solids on the Celite
pad were rinsed with dichloromethane. The combined filtrates were
diluted with water, and the separated aqueous layer was extracted
twice with dichloromethane. The combined organic layers were
washed with brine, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure to give 9.78 g (93%) com-
1
pound 16 as a beige solid. H NMR (400 MHz, CDCl3) δ 7.67-
7.64 (m, 2H), 7.41-7.34 (m, 5H), 7.20-7.16 (m, 2H), 6.10 (br t,
1H), 5.42 (t, 1H, J ) 7.1 Hz), 4.95 (dd, 1H, J ) 9.1 and 6.6 Hz),
4.51 (dd, 1H, J ) 8.7, 7.9 Hz), 3.38-3.33 (m, 2H), 1.59 (m, 2H),
0.94 (t, 3H, 7.1 Hz). 13C NMR (101 MHz, CDCl3) δ 166.9 (C),
138.3 (C), 134.7 (C), 131.7 (C), 129.8 (CH), 129.8 (CH), 128.7
(CH), 127.0 (CH), 119.9 (CH), 73.2 (CH2), 62.4 (CH), 42.0 (CH2),
23.0 (CH2), 11.7 (CH3). Anal. Calcd for C18H20N2O4S: C, 58.98;
H, 5.59; N, 7.77; S, 8.90. Found: C, 58.92; H, 5.54; N, 7.53; S,
8.86.
Benzoic Acid 1-[2-Phenyl-2-(4-propylcarbamoylphenylamino)-
ethyl]-pyrrolidin-3-yl Ester (17). Triethylamine (1.55 mL, 11.10
mmol) was added to a slurry of benzoic acid pyrollidin-3-yl-ester
hydrochloride (2.52 g, 11.10 mmol) and compound 16 (2.00 g, 5.55
mmol) in acetonitrile (20 mL) at room temperature. After 1 h 40
min, 1 N aqueous hydrochloric acid (25 mL) was added, and the
resulting mixture was stirred for 15 min. Water was added, and
the acetonitrile was evaporated under reduced pressure. This
aqueous solution was extracted repeatedly with ethyl acetate. The
combined organic layers were washed with brine, dried over
Acknowledgment. The authors thank Dr. Tamim Braish,
Professors Steven Ley (Cambridge University), and David
Collum (Cornell University) for helpful discussions.
Supporting Information Available: 1H and 13C NMR spectra
for compounds 9 and 13-17. This material is available free of
JO052060Z
J. Org. Chem, Vol. 71, No. 3, 2006 1261