1
1
powder (69 mg, 70%), H NMR (400 MHz, CD3OD) δ 8.46
give compound 17 (0.5 g, 92%) as a white powder, H NMR
(1H, d, J 13.5 Hz), 7.99 (1H, dd, J 7.6, 1.4 Hz), 7.90–7.78 (5H,
m), 7.62–7.51 (3H, m), 7.38–7.34 (1H, m), 7.27 (2H, d, J 8.8
Hz); 13C NMR (100 MHz, CD3OD) δC 158.86, 143.44, 136.56,
134.46, 134.33, 134.20, 133.64, 133.54, 132.44, 130.50, 130.37,
128.44, 128.31, 122.63, 122.59; 31P NMR (162 MHz, CD3OD)
δP 11.77; MALDI-FTMS, Calc. for C19H15O7PSNa: 441.0168
(MNaϩ). Found: 441.0176.
(400 MHz, CD3OD) δ 8.62 (1H, br s), 8.46 (1H, t, J 1.4 Hz),
8.16 (1H, d, J 7.6 Hz), 8.01 (1H, d, J 7.6 Hz), 7.57 (1H, t, J 7.6
Hz), 2.93, 2.92 (3H, d); 13C NMR (100 MHz, CD3OD–CDCl3
10 : 1) δC 169.96, 169.20, 136.16, 133.76, 132.75, 132.60, 129.99,
129.72, 27.34; MALDI-FTMS, Calc. for C9H10NO3: 180.0655
(MHϩ). Found: 180.0655.
Benzene-1,3-dicarboxylic acid 4-{[4-(benzyloxy)phenyl]-
sulfonyl}phenyl benzyl diester 18. Monobenzyl isophthalate
(0.419 g, 1.6 mmol) was treated with neat thionyl chloride
(1.1 mL, 15 mmol) for 2 h at 50 ЊC. The reaction mixture was
evaporated and dried under vacuum. The residue was dissolved
in CH2Cl2 (20 mL) and treated with phenol 1 (0.51 g, 1.5 mL)
and triethylamine (0.33 mL, 2.4 mmol). After 3 h at room
temperature the solution was washed with water and dried over
anhydrous sodium sulfate. The organic phase was concentrated
6-(3-{Hydroxy[4-(phenylsulfonyl)phenoxy]phosphinyl}benz-
oylamino)hexanoic acid methyl ester 14. A mixture of com-
pound 13 (32 mg, 0.076 mmol) and ε-aminocaproic‡ acid
methyl ester hydrochloride (15 mg, 0.084 mmol) was treated
with EDC–HCl (16.5 mg, 0.084 mmol) in the presence of
triethylamine (24 µL, 0.17 mmol) in CH2Cl2–DMF (2 : 1, 3
mL). After 12 h the reaction mixture was quenched with 1 M
HCl and extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate and concentrated. Chrom-
atography (CH2Cl2–MeOH 4 : 1) afforded 14 as a pale yellow
oil (16 mg, 38%), 1H NMR (400 MHz, CD3OD) δ 8.1 (1H, dt,
J 15.0, 1.5 Hz), 7.82–7.69 (6H, m), 7.57–7.34 (4H, m), 7.15 (2H,
d, J 8.0 Hz), 3.52 (3H, s), 3.40 (2H, m), 2.24 (2H, t, J 8.0 Hz),
1.57–1.48 (4H, m), 1.31–1.27 (2H, m); 13C NMR (100 MHz,
CD3OD) δC 175.87, 169.79, 143.39, 136.89, 135.70, 135.49,
134.38, 131.13, 131.02, 130.62, 130.52, 130.43, 129.36, 129.23,
128.45, 122.60, 51.98, 40.80, 34.66, 30.08, 27.48, 35.69; 31P
NMR (162 MHz, CD3OD) δP 10.24; MALDI-FTMS Calc. for
C26H28NO8PSNa: 568.1165 (MNaϩ). Found: 568.1160.
1
to afford 18 as a white powder (0.86 g, 96%), H NMR (400
MHz, CDCl3) δ 8.84 (1H, t, J 1.4 Hz), 8.35 (2H, dd, J 7.9, 1.8
Hz), 8.00 (2H, d, J 8.8 Hz), 7.99 (2H, d, J 8.8 Hz), 7.62 (1H, t,
J 7.9 Hz), 7.48–7.45 (2H, m), 7.42–7.35 (10H, m), 7.05 (2H, d,
J 9.1 Hz), 5.41 (2H, s), 5.12 (2H, s); 13C NMR (100 MHz,
CDCl3) δC 165.19, 163.51, 162.53, 153.92, 139.79, 135.60,
135.48, 134.87, 134.39, 132.92, 131.31, 130.85, 129.84, 129.08,
128.96, 128.65, 128.58, 128.38, 128.28, 127.38, 122.51, 115.34,
70.27, 67.13; MALDI-FTMS, Calc. for C34H26O7NaS: 601.1291
(MNaϩ). Found: 601.1287.
Benzene-1,3-dicarboxylic acid benzyl 4-(phenylsulfonyl)phenyl
diester 19. Monobenzyl isophthalate (0.768 g, 3.0 mmol) was
activated with thionyl chloride (1.1 mL, 15 mmol) for 2 h. After
SOCl2 was removed by evaporation the residue was redissolved
in chloroform (20 mL) and treated with phenol 3 (0.702 g, 3.0
mmol) and triethylamine (3.3 mL, 24 mmol) in a procedure
analogous to that described for 18. Chromatography (hexane–
6-(3-{Hydroxy[4-(phenylsulfonyl)phenoxy]phosphinyl}benzo-
ylamino)hexanoic acid, 15. Compound 14 (16 mg, 0.029 mmol)
was treated with lithium hydroxide monohydrate (3.7 mg, 0.088
mmol) in acetonitrile–water (4 : 1, 2.5 mL). After 2 h the solvent
was evaporated and the residue was purified by preparative
TLC (CH2Cl2–MeOH 3 : 1) to give 15 (9.3 mg, 60%), 1H NMR
(400 MHz, CD3OD) δ 8.21 (1H, dt, J 12.0, 1.4 Hz), 7.92–7.84
(4H, m), 7.81 (2H, d, J 8.8 Hz), 7.62–7.58 (1H, m), 7.56–7.51
(2H, m), 7.48–7.43 (1H, m), 7.25 (2H, dd, J 9.1, 1.2 Hz), 3.37
(2H, m), 2.17 (2H, t, J 7.3 Hz), 1.69–1.59 (4H, m), 1.44–1.37
(2H, m); 13C NMR (100 MHz, CD3OD) δC 182.91, 143.36,
137.35, 135.92, 135.42, 134.39, 131.30, 130.95, 130.52, 130.43,
130.19, 129.15, 128.44, 127.66, 122.60, 120.08, 41.09, 39.16,
30.32, 28.22, 27.46; 31P NMR (101 MHz, CDCl3) δP 10.3;
MALDI-FTMS Calc. for C25H26NO8PSNa: 554.1014 (MNaϩ).
Found: 554.1029.
1
EtOAc 2 : 1) afforded 19 (1.24 g, 88%) as orange crystals, H
NMR (400 MHz, CDCl3) δ 8.84 (1H, t, J 1.4 Hz), 8.35 (2H, dd,
J 8.0, 1.8 Hz), 8.03 (2H, d, J 8.8 Hz), 7.97 (2H, d, J 7.4 Hz),
7.63–7.58 (2H, m), 7.53 (2H, t, J 8.1 Hz), 7.46 (2H, d, J 6.6 Hz),
7.42–7.36 (5H, m), 5.42 (2H, s); 13C NMR (100 MHz, CDCl3)
δC 165.26, 163.57, 154.27, 141.27, 139.15, 135.54, 134.99,
134.46, 133.36, 131.40, 130.96, 129.49, 129.37, 129.15, 129.02,
128.64, 128.46, 128.35, 127.67, 122.65, 67.20; MALDI-FTMS,
Calc. for C27H20O6NaS: 495.0873 (MNaϩ). Found: 495.0893.
Benzene-1,3-dicarboxylic acid {4-[(4-hydroxyphenyl)sulfonyl]-
phenyl} ester 20. Compound 18 (0.86 g, 1.45 mmol) was
dissolved in chloroform and hydrogenolyzed at 40 psi over Pd
(10% on carbon, 0.3 g). After the reaction was completed
methanol was added and the catalyst was filtered off. The
solvent was removed to give 20 as a white powder (0.55 g, 95%),
1H NMR (400 MHz, CDCl3) δ 8.88 (1H, t, J 1.8 Hz), 8.42–8.36
(2H, m), 8.00 (2H, d, J 8.9 Hz), 7.85 (2H, d, J 8.8 Hz), 7.66 (1H,
Isophthalamic acid methyl benzyl diester 16. Monobenzyl
isophthalate22 (1.55 g, 6.05 mmol) was treated with SOCl2
(2.21 mL, 30.3 mmol) at 50 ЊC for 2 h. After the excess of SOCl2
was evaporated, the residue was dried under vacuum and then
redissolved in CH2Cl2 (10 mL). Methylamine (2.6 mL, 30.3
mmol, 40% aqueous solution) was added at 0 ЊC with stirring.
After 1 h the organic layer was separated and washed with
water and brine. The solvent was removed by evaporation and
the residue chromatographed on silica gel (hexane–EtOAc
1 : 1). Recrystallization from hexane–EtOAc afforded 16 (0.81
t, J 7.9 Hz), 7.38 (2H, d, J 8.8 Hz), 6.93 (2H, d, J 8.8 Hz); 13
C
NMR (100 MHz, CD3OD) δC 168.35, 165.02, 163.78, 155.61,
141.50, 135.92, 135.18, 132.79, 132.41, 132.18, 131.15, 130.55,
130.24, 130.01, 123.99, 117.09; MALDI-FTMS, Calc. for
C20H14O7NaS: 421.0352 (MNaϩ). Found: 421.0335.
1
g, 50%) as white needles, H NMR (400 MHz, CDCl3) δ 8.37
(1H, t, J 1.8 Hz), 8.20 (1H, dt, J 7.7, 1.5 Hz), 8.04 (1H, dt, J 8.4,
1.1 Hz), 7.56–7.36 (6H, m), 6.22 (1H, br s), 5.39 (2H, s), 3.04,
3.02 (3H, d); 13C NMR (100 MHz, CDCl3) δC 167.16, 165.69,
135.65, 134.94, 132.37, 131.85, 130.39, 128.85, 128.62,
128.39, 128.31, 127.50, 67.06, 26.86; MALDI-FTMS Calc. for
C16H16NO3: 270.1125 (MHϩ). Found: 270.1126.
Benzene-1,3-dicarboxylic acid mono[4-(phenylsulfonyl)phenyl]
ester 21. Compound 20 (1.24 g, 2.6 mmol) was dissolved in
chloroform (20 mL) and hydrogenolyzed at 40 psi over Pd (10%
on carbon, 0.3 g). After 6 h, methanol (20 mL) was added and
the catalyst was filtered off. The solvent was evaporated to give
1
Isophthalamic acid 17. Compound 16 (0.81 g, 3 mmol) was
dissolved in MeOH (15 mL) and hydrogenolyzed at 40 psi over
Pd (10% on carbon, 0.3 g). The reaction was completed in 2 h.
The catalyst was filtered off and the solvent was removed to
21 (0.952 g, 96%) as a white crystalline solid, H NMR (400
MHz, CD3OD) δ 8.77 (1H, t, J 1.5 Hz), 8.37 (1H, dt, J 7.9, 1.2
Hz), 8.33 (1H, dt, J 7.9, 1.2 Hz), 8.07 (2H, d, J 8.8 Hz), 7.99
(2H, d, J 7.0 Hz), 7.71–7.64 (2H, m), 7.62–7.58 (2H, m),
7.51 (2H, d, J 8.8 Hz); 13C NMR (100 MHz, DMSO-d6)
δC 166.33, 163.43, 154.29, 140.96, 138.79, 134.69, 134.01,
‡ The IUPAC name for caproic acid is hexanoic acid.
J. Chem. Soc., Perkin Trans. 1, 2001, 2796–2803
2801