Tropos, But Conformationally Stable Biphenyl Derivatives
3
–1
ate and the solvent was removed in vacuo. The residue was purified
by column chromatography over silica gel (DCM/AcOEt, 75:25)
and subsequently by HPLC. The product was obtained as a color-
(logε) = 240 (3.31) nm. CD (DCM): λ (Δε mol–1 dm cm ) = 251
(–36.0), 237 (–7.3), 220 (–82.3), 203 (+124.8) nm. HRMS (ESI):
calcd. for C52
H
70
+
N
8
O
10 [M + H]+ 967.5288; found 967.5288; calc.
1
+
less solid (6 mg, 7%). H NMR (500 MHz, CDCl
3
4
): δ = 7.34 (d,
for [M + Na] 989.5107; found 989.510; calcd for [2M + Na]
1957.0328; found 1957.0356.
3
3
J
N,H = 10.1 Hz, 2 H, NH), 7.17 (dd, JH,H = 8.4, JH,H = 2.5 Hz,
2
5
=
4
4
6
H, HPh), 6.94 (d, JH,H = 8.4 Hz, 2 H, HPh), 6.86 (d, 3JN,H
=
3
4
2
Biphenyl System 4b: The biphenyl system 4f (18 mg, 0.019 mmol)
was dissolved in dichloromethane (10 mL), and trifluoroacetic acid
(0.1 mL, 1.307 mmol) was added. The solution was stirred for two
days at room temperature, and afterwards poured into a dichloro-
methane/water mixture. The organic layer was separated, dried with
magnesium sulfate and the solvent was removed in vacuo. The resi-
due was purified by column chromatography over silica gel (DCM/
AcOEt/MeOH, 75:25:3) and subsequently by HPLC. The product
.2 Hz, 2 H, NH), 5.35 (d, JH,H = 2.2 Hz, 2 H, HPh), 5.17 (d, JH,H
2
17.2 Hz, 2 H, CH
2
-Ph), 5.00 (d, JH,H = 17.2 Hz, 2 H, CH
2
-Ph),
.74 [dd, JH,H = 5.0, JH,H = 4.4 Hz, 2 H, NH-CH-CH(CH ],
.40 (dd, JH,H = 9.9, JH,H = 8.5 Hz, 2 H, NH-CH-CO), 3.74 (s,
H, OCH ), 2.65–2.59 [m, 2 H, CH(CH ], 2.39 (s, 6 H, imid-
), 2.24–2.18 [m, 2 H, CH(CH ], 1.20 (d, JH,H = 6.5 Hz,
), 1.17 (d, JH,H = 6.9 Hz, 6 H, CH-CH ), 0.88 (d,
3
3
3 2
)
3
3
3
3 2
)
3
azole-CH
H, CH-CH
J
3
3 2
)
3
6
3
3
3
3
3
H,H = 6.6 Hz, 6 H, CH-CH ), 0.84 (d, JH,H = 6.8 Hz, 6 H, CH-
1
) ppm. 13C NMR: (125 MHz, CDCl
was obtained as a colorless solid (7 mg, 48%). H NMR (500 MHz,
[D ]MeOD): δ = 7.19 (dd, JH,H = 8.2, JH,H = 2.4 Hz, 2 H, HPh),
4
CH
3
3
): δ = 171.4 (q; C=O),
3
4
1
63.6 (q; C=O), 157.1 (q; CPhOCH
), 129.5 (q; CimidazoleCO), 128.5 (q; CPhPh), 126.6
t; CPh), 126.3 (q; CHCPhCHCH), 124.7 (t; CCPhC), 111.9 (t; CPh),
3
), 144.7 (q; CimidazoleCH), 135.2
6
.87 (d, JH,H = 8.4 Hz, 2 H, HPh), 5.44 (d, 4JH,H = 2.0 Hz, 2 H,
Ph), 5.30 (d, 2 -Ph), 5.11 (d, 2
H,H = 17.8 Hz, 2 H, CH
7.3 Hz, 2 H, CH -Ph), 4.85–4.84 [m, 2 H, NH-CH-CH(CH
.19 (d, JH,H = 11.2 Hz, 2 H, NH-CH-CO), 2.34–2.24 [m, 4 H,
3
(q; CimidazoleCH
3
H
J
2
H,H
J =
(
1
4
2
3 2
) ],
6
0.6 (t; COCHNH), 55.9 (p; OCH
3
), 51.7 (t; imidazoleCHNH),
], 30.6 [t;
], 19.4 [p;
], 18.71 [p; imidazoleCHCH(CH ], 17.1 [p;
], 10.0 (p; imidazoleCH ) ppm. IR (ATR):
ν˜ = 3373, 2962, 2930, 2873, 1666, 1591, 1500, 1462, 1420, 1388,
3
46.1 (s; CH Ph), 32.1 [t; imidazoleCHCH(CH )
2
3 2
3
CH(CH
3
)
2
], 2.32 (s, 6 H, imidazole-CH
3
), 1.20 (d, JH,H = 6.5 Hz,
), 1.14 (d, JH,H = 6.6 Hz, 6 H, CH-CH ), 0.95 (d,
), 0.9 (d, JH,H = 6.9 Hz, 6 H, CH-
) ppm. C NMR (125 MHz, [D ]MeOD): δ = 174.50 (q;
C=O), 166.60 (q; C=O), 155.53 (q; Ph-OH), 146.61 (q;
), 130.58 (q; CimidazoleCO),
), 128.02 (t; CPh), 127.86 (q; CPhPhenyl), 126.35
t; CPh), 118.01 (t; CPh), 63.65 (t; COCHNH), 52.81 (t; imid-
azoleCHNH), 47.33 (s; CH Ph), 35.43 [t; CHCH(CH ], 31.32 [t;
CHCH(CH ], 21.20 [p; CH(CH ], 20.08 [p; CH(CH ], 18.96
p; CH(CH ], 18.75 [p; CH(CH ], 10.30 (p; imidazoleCH ) ppm.
COCHCH(CH
COCHCH(CH
imidazoleCHCH(CH
3
3
)
)
2
3 2
], 19.6 [p; COCHCH(CH )
3
6
H, CH-CH
3
3
2
3 2
)
3
3
J
H,H = 6.9 Hz, 6 H, CH-CH
3
3
)
2
3
1
3
CH
3
4
–
1
C
1
343, 1246, 1189, 1133, 1087, 1026, 956, 889, 809, 751 cm . UV/
C
imidazoleCH), 137.00 (q; CimidazoleCH
3
Vis (CH CN): λmax (logε) = 285 (3.39), 249 (3.87), 215 (4.15), 194
3
4.29) nm. CD (DCM): λ (Δε mol–1 dm cm ) = 274 (–0.6), 253
3
–1
128.22 (q; CPhCH
2
(
(
(
–7.6), 242 (–2.9), 225 (–16.0), 209 (+18.3) nm. HRMS (ESI): calcd.
+
2
3 2
)
for C44
+
H
58
N
8
O
6
[M + H] 795.4551; found 795.4592; calc. for [M
+
3
)
2
3
)
2
3 2
)
Na] 817.4372; found 817.4422.
[
3
)
2
3
)
2
3
IR (ATR): ν˜ = 3353, 2962, 2927, 1656, 1591, 1499, 1463, 1421,
Biphenyl System 4f: The imidazole macrocycle
.031 mmol), the dibromide 8f (24 mg, 0.042 mmol) and cesium
carbonate (99 mg, 0.304 mmol) were dissolved in acetonitrile
60 mL) under argon. The reaction mixture was placed in a 90 °C
oil bath and was stirred for four hours. After cooling to room tem-
perature, the solution was poured into an ethyl acetate/water mix-
ture. The organic phase was separated, dried with magnesium sulf-
ate, and the solvent was removed in vacuo. The residue was purified
by column chromatography over silica gel (DCM/AcOEt/MeOH,
9 (17 mg,
1
7
2
388, 1372, 1342, 1261, 1239, 1136, 1115, 1027, 995, 944, 892, 812,
0
–
1
80, 722 cm . UV/Vis (CH
3
CN): λmax (logε) = 337 (1.85),
88 (2.58), 245 (3.31), 217 (3.51) nm. CD (DCM):
λ
(
–
1
3
–1
(
Δε mol dm cm ) = 284 (–4.5), 273 (–3.3), 251 (–32.7), 240
(
C
–19.0), 225 (–57.0), 209 (+88.3) nm. HRMS (ESI): calcd. for
[M + H]+ 767.4238; found 767.4238; calcd. for [M +
42
H
54
N
8
O
6
+
Na] 789.4059; found 789.4061.
Crystal Structure Analysis of 4a: The crystal was mounted on nylon
loops in inert oil. Data were collected with a Bruker AXS D8
Kappa diffractometer with an APEX2 detector (monochromated
7
5:25:5) and subsequently by HPLC. The product was obtained as
1
3
a colorless solid (22 mg, 74%). H NMR (500 MHz, CDCl ): δ =
3
3
7.34 (d, JN,H = 9.9 Hz, 2 H, NH), 7.25 (d, JH,H = 8.0 Hz, 2 H,
Mo-K
α
radiation, λ = 0.71073 Å) at 100 K. The structures were
4
H
Ph), 7.21 (dd, 3JH,H = 8.3, JH,H = 2.0 Hz, 2 H, HPh), 6.89 (d,
[22]
solved by direct methods (SHELXS-97) and refined anisotropi-
3
4
J
H,H = 5.4 Hz, 2 H, NH), 5.51 (d, JH,H = 1.9 Hz, 2 H, HPh), 5.24
2
[23]
cally by full-matrix least-squares on F (SHELXL-97). Absorp-
tion corrections were performed semiempirically from equivalent
reflections on the basis of multiple scans (Bruker AXS APEX2).
Hydrogen atoms were refined using a riding model or rigid methyl
groups. Hydrogen atom positions of OH and NH groups were
taken from a Fourier difference map and refined freely with an
isotropic displacement parameter constrained to 1.2 and 1.5 fold
of the Uij of the corresponding N and O atom, respectively. OH
bond lengths and H–O–H bond angles of the water molecules were
restrained to be equal (SADI). The absolute structure parameter
2
-Ph), 5.01 (d, 2JH,H = 17.8 Hz, 2 H,
], 4.42–4.38 (m, 2
], 2.38 (s, 6 H, imid-
(
d, JH,H = 17.5 Hz, 2 H, CH
CH -Ph), 4.78–4.77 [m, 2 H, NH-CH-CH(CH
H, NH-CH-CO), 2.67–2.61 [m, 2 H, CH(CH
azole-CH ), 2.25–2.18 [m, 2 H, CH(CH ], 1.33 [s, 18 H, PhO-
CO)OC(CH ], 1.20 (d, JH,H = 6.8 Hz, 6 H, CH-CH ), 1.18 (d,
), 0.88 (d, JH,H = 6.9 Hz, 6 H, CH-
2
2
3 2
)
)
3 2
3
3 2
)
3
(
3
)
3
3
3
3
J
H,H = 6.8 Hz, 6 H, CH-CH
CH HH = 6.9 Hz, 6 H, CH-CH
), 0.85 (d, 3
125 MHz, CDCl ): δ = 171.62 (q; C=O), 163.43 (q; C=O), 150.36
q; O(C=O)O], 148.03 (q; CPh), 144.61 (q; CimidazoleCH), 135.11 (q;
3
13
3
J
3
) ppm. C NMR:
(
[
3
C
C
imidazoleCH
3
), 132.39 (q; CPhPh), 131.26 (q; CPhCH
imidazoleCO), 126.12 (t; CPh), 125.58 (t; CPh), 123.31 (t; CPh), 82.85
], 60.72 (t; COCHNH), 51.84 (t; imidazoleCHNH),
6.1 (s; CH Ph), 32.14 [t; imidazoleCHCH(CH ], 30.57 [t;
], 19.65 [p;
], 18.84 [p; imid-
], 17.05 [p; imidazoleCHCH(CH ], 9.79 (p;
2
), 129.75 (q;
[24]
ϫ (Flack parameter ) was ambiguous due to the lack of heavy
atoms. Consequently, the absolute structure was assigned by refer-
ence to a known configuration of a chiral centre that did not
change during the syntheses. A selection of crystallographic param-
eters for compound 4a are found in Table 3.
3 3
[q; C(CH )
4
2
3 2
)
COCHCH(CH
COCHCH(CH
3
)
2
)
2
3
], 27.43 [p; PhO(CO)OC(CH
3 3
)
3
], 19.51 [p; COCHCH(CH
3 2
)
azoleCHCH(CH
imidazoleCH
)
2
3
)
2
CCDC-905893 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
3
) ppm. IR (ATR): ν˜ = 3357, 2963, 2929, 2873, 1759,
666, 1593, 1501, 1462, 1423, 1390, 1370, 1344, 1276, 1250, 1218,
147, 1051, 945, 891, 811, 776, 737 cm . UV/Vis (CH CN): λmax
3
1
1
–1
Eur. J. Org. Chem. 2013, 2325–2333
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2331