Induced Fit Selection of a Barbiturate Receptor
FULL PAPER
Data for 3 in Complex 3:4: 1H NMR (500 MHz, CDCl3, 10 m):
δ ϭ 13.71 (s, 2 H); 2.00 (m, 4 H); 1.33Ϫ1.16 (m, 8 H); 0.85 (t, 3J ϭ
7.2 Hz, 6 H, CH3).
(m, 9 H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 172.2; 164.6; 159.7;
149.9; 149.2; 140.5; 135.6; 117.2; 110.3; 109.6; 68.7; 37.5; 31.8; 29.5;
29.4; 29.0; 25.9; 25.3; 22.6; 14.0. Ϫ FAB-MS: m/z 813.6 [M ϩ H]ϩ
(100%). Ϫ C48H72N6O5 (813.13): calc. C 70.9, H 8.92; found
C 70.79, H 8.98.
Dimethyl 5-Decyloxyisophthalate (Scheme 2): To a flask charged
with dimethyl 5-hydroxyisophthalate (8.74 g, 41.48 mmol, 115 mol-
%), 1-bromodecane (7.99 g, 36.10 mmol, 100 mol-%), K2CO3
(7.48 g, 54.12 mmol, 150 mol-%), and DMF (36 mL, 1 ) was ad-
ded, and the mixture stirred at room temperature for 48 h. Et2O
(150 mL) was added and the organic phase washed twice with sat.
aq. brine. The ether layer was dried with MgSO4, filtered, evapo-
rated to dryness, and purified by chromatography (SiO2; EtOAc/
hexane, 10:90 Ǟ 15:85) to provide dimethyl 5-decyloxyisophthalate
(5.90 g, 41% yield) as a white powder. Ϫ M.p. 47Ϫ48 °C. Ϫ IR
(thin film): ν˜ ϭ 2953 cmϪ1, 2920, 2841, 1715, 1583, 1454, 1423,
1334, 1302, 1237, 1216, 1112, 1099, 1048, 1037, 1005, 994, 870,
788, 757, 720. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 8.24 (t, J ϭ
1.4 Hz, 1 H); 7.72 (d, J ϭ 1.4 Hz, 2 H); 4.04 (t, J ϭ 6.5 Hz, 2 H);
3.92 (s, 6 H); 1.76 (m, 2 H); 1.26 (m, 14 H); 0.87 (t, J ϭ 6.4 Hz,
3 H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 166.3; 159.3; 131.77;
122.8; 119.9; 68.7; 52.4; 32.0; 29.6; 29.4; 29.2; 26.0; 22.7; 14.2. Ϫ
EI-MS: m/z 351.1 ([M ϩ H]ϩ, 100%). Ϫ C20H30O5 (350.46): calc.
C 68.55, H 8.63; found C 68.52, H 8.66.
Formation of 7 by Oxidative Coupling of 4: To a solution of pre-
formed 3:4 (1: 0.05 mmol, 7.0 mg; 2: 0.1 mmol, 10.9 mg; 3:
0.05 mmol, 12.0 mg, aged for 2 days under argon) in [D]chloroform
(5 mL, 10 m), was added NEt3 (10.1 mg, 0.1 mmol, 200 mol-%)
and the solution allowed to age under an oxygen atmosphere. After
6 days at room temp., 3:4 was quantitatively oxidized to 32:7, as
1
followed by H-NMR spectroscopy.
1
Data for 7 in Complex 32:7: H NMR (200 MHz, CDCl3, 10 m):
δ ϭ 10.50 (s, 4 H, H-N); 8.35 (dd, 3JH6ϪH5 ϭ 5.4 Hz, 4JH6ϪH4 ϭ
1.2 Hz, 4 H, H-6); 7.58 (ddd, 3JH4ϪH3 ϭ 7.8 Hz, 3JH4ϪH5 ϭ 7.2 Hz,
4JH4ϪH6 ϭ 1.7 Hz, 4 H, H-4); 7.12 (d, 3JH3ϪH4 ϭ 8.3 Hz, 4 H, H-3);
6.79 (ddd, 3JH5ϪH6 ϭ 5.5 Hz, 3JH5ϪH4 ϭ 5.9 Hz, 4JH5ϪH3 ϭ 0.8 Hz,
4 H, H-5); 5.20 (s, 2 H, H-2Ј); 2.95 (d, 2J ϭ 13.9 Hz, 4 H, CH2);
2
2.19 (d, J ϭ 13.9 Hz, 4 H, CH2); 1.02 (s, 6 H, CH3); 0.72 (s, 6 H,
CH3).
1
Data for 3 in Complex 32:7: H NMR (200 MHz, CDCl3, 10 m):
δ ϭ 14.42 (s, 4 H); 2.15 (m, 8 H); 1.40Ϫ1.10 (m, 16 H); 0.82 (t,
N,NЈ-Bis(6-aminopyridin-2-yl)-5-decyloxyisophthalamide (5):[16] To 3J ϭ 6.6 Hz, 12 H).
a solution of 2,6-diaminopyridine (recrystallized from boiling
CHCl3) (5.00 g, 45.82 mmol, 800 mol-%) in dry THF (46 mL, 1 )
at Ϫ78 °C was added a 1.6 solution of nBuLi (44.20 mmol,
26.3 mL) in hexane. After 20 min at Ϫ78 °C, a solution of dimethyl
Acknowledgments
5-decyloxyisophthalate (2.00 g, 5.72 mmol, 100 mol-%) in dry THF
(20 mL) was added dropwise. The reaction mixture was stirred at
Ϫ78 °C for 8 h and then gradually warmed to room temp. and
stirred over night. The reaction was then quenched with a 1 solu-
tion of NaHCO3 (100 mL) and extracted with EtOAc. The com-
bined organic extracts were washed with sat. aq. brine and water,
dried with MgSO4, filtered, evaporated to dryness, and purified
using flash chromatography (SiO2; EtOAc/hexane, 2:1) to give
This work was supported by the CNRS and by a predoctoral fel-
lowship (V. B.) from the Forschungszentrum Karlsruhe GmbH.
[1]
[1a] B. Hasenknopf, J.-M. Lehn, G. Baum, B. Kneisel, D. Fenske,
[1b]
Angew. Chem. Int. Ed. Engl. 1996, 35, 1838. Ϫ
B. Hasenk-
nopf, J.-M. Lehn, N. Boumediene, A. Dupont-Gervais, A. Van
Dorsselaer, B. Kneisel, D. Fenske, J. Am. Chem. Soc. 1997,
119, 10956.
[2]
[3]
[4]
M. Albrecht, O. Blau, R. Fröhlich, Chem. Eur. J. 1999, 5, 48.
I. Huc, J.-M. Lehn, Proc. Natl. Acad. Sci. USA 1997, 94, 2106.
P. A. Brady, J. K. M. Sanders, J. Chem. Soc., Perkin Trans. 1
1997, 3237; Chem. Soc. Rev. 1997, 26, 327.
N,NЈ-bis(6-aminopyridin-2-yl)-5-decyloxyisophthalamide
(5)
(2.63 g, 91% yield) as a pale yellow powder. Ϫ M.p. 132Ϫ133 °C.
Ϫ IR (thin film): ν˜ ϭ 3362 cmϪ1, 3205, 2951, 2923, 2854, 1681,
1620, 1593, 1538, 1456, 1337, 1303, 1247, 1166, 1134, 1051, 989,
[5] [5a]
A. V. Eliseev, M. I. Nelen, J. Am. Chem. Soc. 1997, 119,
[5b]
1147. Ϫ
4, 825.
A. V. Eliseev, M. I. Nelen, Chem. Eur. J. 1998,
1
864, 788, 744, 722, 707. Ϫ H NMR (200 MHz, [D6]DMSO): δ ϭ
[6]
10.22 (s, 2 H); 8.11 (s, 1 H); 7.60 (d, J ϭ 0.5 Hz, 2 H); 7.41 (m,
4 H); 6.28 (dd, J ϭ 6.5 Hz, 1.5 Hz, 2 H); 5.79 (br. s, 4 H); 4.10 (t,
J ϭ 5.3 Hz, 2 H); 1.74 (m, 2 H); 1.25 (m, 14 H); 0.84 (t, J ϭ 6.4 Hz,
3 H). Ϫ 13C NMR (50.3 MHz, [D6]DMSO): δ ϭ 164.5; 158.7;
158.5; 150.2; 138.9; 135.6; 118.8; 116.9; 104.1; 101.8; 67.9; 31.2;
28.9; 28.6; 28.5; 25.4; 22.0; 13.9. Ϫ FAB-MS: m/z 505.3 [M ϩ H]ϩ
(100%). Ϫ C28H36N6O3 (504.63): calc. C 66.64, H 7.19; found
C 66.48, H 7.31.
B. Klekota, M. H. Hammond, B. L. Miller, Tetrahedron Lett.
1997, 38, 8639.
[7]
[8]
H. Hioki, C. Still, J. Org. Chem. 1998, 63, 904.
M. Crego Calama, R. Hulst, R. Fokkens, N. M. M. Nibbering,
P. Timmerman, D. N. Reinhoudt, Chem. Commun. 1998, 1021.
[9]
[9a]
For recent reviews see:
A. Ganesan, Angew. Chem. Int. Ed.
1998, 37, 2828; Ϫ [9b] A. V. Eliseev, Current Opinion Drug. Disc.
[9c]
Develop. 1998, 1, 106; Ϫ
A. V. Eliseev, J.-M. Lehn, Current
Top. Microbiol. Immuno., in press.
[10] [10a]
[10b]
D. F. Koshland Jr., Adv. Enzymol. 1960, 22, 45; Ϫ
A.
Fehrst, Enzyme structure and mechanism, 2nd ed., W. H. Free-
5-Decyloxy-N,NЈ-bis[6-(decanoylamino)pyridin-2-yl]-
isophthalamide (6): To a solution of 5 (0.5 g, 0.99 mmol, 100 mol-
%) and triethylamine (0.20 g, 1.98 mol, 200 mol-%) in dry THF
(20 mL) was added dropwise a solution of decanoyl chloride
(0.38 g, 1.99 mmol, 200 mol-%) in THF (5 mL) at 0°C and the reac-
tion stirred for 1 h, before warming to room temp. The reaction
mixture was filtered, evaporated to dryness, and applied to a col-
umn (SiO2; EtOAc/hexane, 1:3) to provide 6 (0.68 g, 84% yield) as
a white powder. Ϫ M.p. 158Ϫ159 °C. Ϫ IR (thin film): ν˜ ϭ 3405
cmϪ1, 3300, 2956, 2924, 2854, 1674, 1586, 1514, 1451, 1378, 1334,
1315, 1301, 1243, 1155, 1121, 1051, 883, 801, 722. Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 8.65 (br. s, 2 H); 8.44 (br. s, 2 H); 7.83 (m,
5 H); 7.55 (t, J ϭ 8.0 Hz, 2 H); 7.44 (s, 2 H); 3.85 (t, J ϭ 6.4 Hz,
2 H); 2.33 (t, J ϭ 7.4 Hz, 4 H); 1.65 (m, 6 H); 1.23 (m, 38 H); 0.84
man & Co, New-York, 1985.
[11]
[12]
[11a]
For two examples, see:
J. C. Adrian, C. G. Wilcox, J. Am.
[11b]
Chem. Soc. 1992, 114, 1398; Ϫ
T. Hayashi, T. Asai, H.
Hokazono, H. Ogoshi, J. Am. Chem. Soc. 1993, 115, 12210; see
also references in these papers.
The identification of these compounds is based on mass spec-
trometry and NMR analysis of the product mixture using 1 and
2 in various proportions.
[13]
[14]
[15]
S. M. Nelson, C. V. Knox, M. McCann, J. Chem. Soc., Dalton
Trans. 1981, 1669.
E. Fischer, A. Dilthey, Justus Liebigs Ann. Chem. 1904, 335,
336.
The synthesis of the barbiturate receptor 6 is achieved in 3 steps
starting from dimethyl 5-hydroxyisophthalate, which is O-alkyl-
ated with decyl bromide and K2CO3 in DMF at room temp.
The resulting dimethyl-5-decyloxy-isophthalate is then treated
with an access of 2,6-diaminopyridine monolithium salt in dry
Eur. J. Org. Chem. 1999, 3089Ϫ3094
3093