An Acyclic Phane Receptor Recognizing Catechins
1
(1.31 g, 36% for 2 steps) as a white solid: mp 90 °C; H NMR
(500 MHz, CDCl3) δ 9.01 (1H, t, J ) 1.9 Hz), 8.47 (2H, dd, J )
1.9, 8.0 Hz), 7.70 (1H, t, J ) 8.0 Hz), 7.45 (2H, t, J ) 8.0 Hz),
7.30 (2H, br d, J ) 8.0 Hz), 7.29 (2H, br s), 7.18 (2H, br dd, J )
2.5, 8.0 Hz), 4.76 (4H, d, J ) 6.1 Hz), and 1.76 (2H, t, J ) 6.1
Hz); 13C NMR (125 MHz, CDCl3) δ 164.3 (C), 150.9 (C), 142.9
(C), 135.0 (CH), 131.7 (CH), 130.3 (CH), 129.7 (CH), 129.1 (C),
124.4 (CH), 120.7 (CH), 120.0 (CH), and 64.7 (CH2); IR (KBr)
3317, 3088, 3063, 2925, 2880, 1734, 1607, 1590, 1490, and 1448
cm-1; HR-EI-MS, calcd for C22H18O6 (M+) 378.1103, found
378.1091.
Bis[3′-(bromomethyl)phenyl] Isophthalate (13). Carbon tet-
rabromide (CBr4) (3.08 g, 9.30 mmol) and triphenylphosphine
(Ph3P) (1.95 g, 7.44 mmol) were added to a solution of diol 12
(1.17 g, 3.10 mmol) in CH2Cl2 (60 mL) at 25 °C. The solution
was stirred at 25 °C for 15 min, and then CBr4 (0.308 g, 0.929
mmol) and Ph3P (0.195 g, 0.743 mmol) were added. The solution
was stirred for 30 min then methanol (6.3 mL) was added and the
solution was stirred an additional 10 min before the solvent was
removed in vacuo. The residue was purified by flash column
chromatography (SiO2, 10:1 to 4:1 hexane-EtOAc) to give
dibromide 13 (1.34 g, 86%) as a white solid: mp 110 °C; 1H NMR
(500 MHz, CDCl3) δ 9.01 (1H, dt, J ) 0.6, 1.8 Hz), 8.47 (2H, dd,
J ) 1.8, 7.9 Hz), 7.71 (1H, dt, J ) 0.6, 7.9 Hz), 7.43 (2H, t, J )
8.3 Hz), 7.33 (2H, ddd, J ) 1.2, 1.6, 8.3 Hz), 7.32 (2H, dd, J )
1.6, 2.1 Hz), 7.20 (2H, ddd, J ) 1.2, 2.1, 8.3 Hz), and 4.52 (4H,
s); 13C NMR (125 MHz, CDCl3) δ 164.0 (C), 150.8 (C), 139.5
(C), 135.1 (CH), 131.8 (CH), 130.2 (C), 129.9 (CH), 129.2 (CH),
126.7 (CH), 122.3 (CH), 121.7 (CH), and 32.4 (CH2); IR (KBr)
3078, 3037, 1744, 1609, 1589, 1483, 1450, and 1436 cm-1; HR-
EI-MS, calcd for C22H16Br2O4 (M+) 501.9415, found 501.9431.
Bis[3′-(trimethylammoniomethyl)phenyl] Isophthalate Dibro-
mide (9). Trimethylamine (30% in water) (5 mL) was added to a
solution of dibromide 13 (0.388 g, 0.770 mmol) in acetonitrile (20
mL) at 0 °C. The solution was stirred for 30 min, and then
trimethylamine (30% in water) (5 mL) was added. The solution
was stirred at 0 °C an additional 30 min before the solvent was
removed in vacuo. The residue was recrystallized twice from
methanol-EtOAc to give quaternary ammonium salt 9 (0.220 g,
46%) as a white solid: mp 238-239 °C dec; 1H NMR (500 MHz,
D2O) δ 8.80 (1H, t, J ) 1.5 Hz, C2-H), 8.35 (2H, dd, J ) 1.5, 8.0
Hz, C4(6)-H), 7.64 (1H, t, J ) 8.0 Hz, C5-H), 7.50 (2H, t, J ) 8.3
Hz, C5′-H), 7.37 (2H, br d, J ) 8.3 Hz, C4′-H), 7.34 (2H, br d, J
) 8.3 Hz, C6′-H), 7.33 (2H, br s, C2′-H), 4.38 (4H, s, C1”-H),
and 2.95 (18H, s, N-Me); 13C NMR (125 MHz, D2O) δ 166.5 (C),
150.6 (C), 135.6 (CH), 131.6 (CH), 131.2 (CH), 130.8 (CH), 129.8
(CH), 129.4 (C), 129.2 (C), 126.0 (CH), 124.3 (CH), 68.9 (CH2),
and 52.6 (CH3); IR (KBr) 3022, 2961, 1740, 1609, 1588, 1490,
and 1449 cm-1; HR-FAB-MS, calcd for C28H34BrN2O4 (M+ - Br)
541.1702, found 541.1703.
Bis[3′-(hydroxymethyl)phenyl] Phthalate (16). Pyridine (2.35
mL, 29.1 mmol) and phthaloyl chloride (1.40 mL, 9.70 mmol) were
added to a solution of 3-hydroxybenzaldehyde (2.31 g, 18.9 mmol)
in CH2Cl2 (150 mL) at 0 °C. The solution was stirred at 0 °C for
1 h, then 25 °C for 3 h. The reaction mixture was poured into a
flask with ice, then extracted with EtOAc. The organic phase was
washed with 1 M aq HCl, satd aq NaHCO3, and brine, then dried
over anhydrous MgSO4. The dried solution was filtered and the
filtrate was concentrated in vacuo. The residue was purified by flash
chromatography (SiO2, 5:1 to 2:1 hexane-EtOAc) to give bisester
(2.76 g) with a byproduct.
NaBH4 (0.294 g, 7.37 mmol, purity 95%) was added to the
solution of the bisester in ethanol (70 mL) and THF (30 mL) at 0
°C. The solution was stirred at 0 °C for 30 min. The reaction was
quenched by adding 1 M aq HCl dropwise. The resulting mixture
was diluted with EtOAc, washed with 1 M aq HCl, satd aq NaHCO3
and brine, then dried over anhydrous MgSO4. The dried solution
was filtered and the filtrate was concentrated in vacuo. The residue
was purified by flash column chromatography (SiO2, 1:1 to 2:3
FIGURE 8. The proposed complex structure 15 formed by the meta-
substituted receptor 9 (space filling model) and GCg 3 (stick model).
between C2-H of 9 and C2′′(6′′)-H of 1 in addition to the cross
peaks between the ammonium moieties of 9 and the B-ring/
galloyl moieties of 1 (Figure 7b). These results suggest that
plural complex structures with similar energies exist between
9 and 1. From the binding studies and the NOESY experiments,
it is probable that the conformational matching effect such as
in the case of the 2,3-trans-gallate-type catechins is not gained
in the complex between 9 and the 2,3-cis-gallate-type catechins
because of the conformational difference between the 2,3-cis-
gallate-types and the 2,3-trans-gallate-types. Similar reasons
might also account for the larger binding constants of 10 for
the 2,3-trans-gallate-type catechins compared to those for the
2,3-cis-gallate type catechins.
In this study, we synthesized two water-soluble acyclic phane
receptors for gallate-type catechins and evaluated their binding
abilities in water. It was found that the meta-substituted receptor
9 showed the best affinity for the gallate-type catechins, the
2,3-trans-types (3 and 4) in particular. The receptor 9 is certain
to achieve recognition by the difference in both the hydropho-
bicity and the conformation of the catechin molecules. It is very
interesting that the acyclic phane receptor 9, a fairly simple
molecule, can distinguish differences in the structures of the
catechin analogues. It is expected that the chemical structure
of 9 can be applied to chemical sensor systems.
Experimental Section
Bis[3′-(hydroxymethyl)phenyl] Isophthalate (12). Pyridine
(2.34 mL, 28.9 mmol) and isophthaloyl chloride 11 (1.95 g, 9.62
mmol) were added to a solution of 3-hydroxybenzaldehyde (2.30
g, 18.8 mmol) in CH2Cl2 (200 mL) at 0 °C. The solution was stirred
at 0 °C for 30 min, then 25 °C for 2 h. The reaction mixture was
poured into a flask with ice and extracted with ethyl acetate
(EtOAc). The organic phase was washed with 1 M aq HCl, satd aq
sodium hydrogencarbonate (NaHCO3), and brine, then dried over
anhydrous magnesium sulfate (MgSO4). The dried solution was
filtered and the filtrate was concentrated in vacuo. The residue was
solved in CH2Cl2. Hexane was added to the solution to form a white
precipitate, which was isolated by a Kiriyama funnel.
Sodium borohydride (NaBH4) (0.241 g, 6.05 mmol, purity 95%)
was added to the solution of the precipitate in ethanol (120 mL)
and CH2Cl2 (50 mL) at 0 °C. The solution was stirred at 0 °C for
1.5 h. The reaction was quenched by adding 1 M aq HCl dropwise.
The resulting mixture was diluted with EtOAc, washed with 1 M
aq HCl, satd aq NaHCO3, and brine, then dried over anhydrous
MgSO4. The dried solution was filtered and the filtrate was
concentrated in vacuo. The residue was purified by flash column
chromatography (SiO2, 1:1 to 2:3 hexane-EtOAc) to give diol 12
J. Org. Chem. Vol. 73, No. 13, 2008 4853
Hayashi, Nobuyuki
