A. Spa¨th, B. Ko¨nig / Tetrahedron 66 (2010) 1859–1873
1871
After vacuum drying the crude product was purified by column
chromatography on silica gel with ethyl acetate/ethanol as eluent
(Rf ca. 0.3 in EE/EtOH 6/1).
diethylether was decanted off, and the process was repeated. The
product was dried in the vacuum to give a fine hygroscopic, faintly
yellow powder. The yield is nearly quantitative.
4.4.1. 14-[4-[2-(tert-Butyloxycarbonyl)-3-(pyrrole-2-carbonyl)-gua-
nidino-methyl]-benzyl]-6,7,9,10,13,14,15,16,18,19,21,22-dodecahydro-
12H-5,8,11,17,20,23-hexaoxa-14-aza-benzocycloheneicosene-2,3-di-
carboxylic acid dimethyl ester (30). Reacting 4d (136 mg,
0.20 mmol) after GP VII a yellow glass is obtained (125 mg,
0.151 mmol, 76%). Ethanol/ethyl acetate 1/6 was used for purifica-
4.5.1. 14-[4-[2-(Pyrrole-2-carbonyl)-guanidino-methyl]-benzyl]-
6,7,9,10,13,14,15,16,18,19,21,22-dodecahydro-12H-5,8,11,17,20,23-hex-
aoxa-14-aza-benzocycloheneicosene-2,3-dicarboxylic acid dimethyl
ester hydrochloride (32). Deprotection of 30 (83 mg, 0.10 mmol) by
GP VII gives a yellow, hygroscopic, glassy solid (68 mg, 0.094 mmol,
94%). 1H NMR (400 MHz, CDCl3):
d
[ppm]¼3.12–3.30 (m, 4H), 3.49–
tion. 1H NMR (400 MHz, CDCl3):
d
[ppm]¼149–1.51 (s, 9H), 2.62–
3.69 (m, 8H), 3.71–3.96 (m, 8H), 3.84 (s, 6H), 4.06–4.25 (m, 4H), 4.41
(m, 2H), 4.52 (m, 2H), 6.21 (m, 1H), 6.90–7.11 (m, 5H), 7.28–7.32 (m,
3H), 9.71 (br s, 1H), 10.30 (br s, 1H), 11.12 (br s, 1H); 13C NMR
2.81 (m, 4H), 3.49–3.70 (m, 10H), 3.71–3.80 (m, 4H), 3.83–3.96 (m,
4H), 3.82 (s, 6H), 4.11–4.21 (m, 4H), 4.61 (m, 2H), 6.21 (m, 1H), 6.85
(m, 1H), 6.95 (m, 1H), 7.17 (s, 2H), 7.21–7.33 (m, 4H), 8.62 (br s, 1H),
9.39 (br s, 1H), 12.39 (s, 1H); 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
[ppm]¼44.1 (ꢀ, 1C), 52.5 (ꢀ, 2C), 52.8 (þ, 2C),
57.1 (ꢀ, 1C), 65.0 (ꢀ, 2C), 68.1 (ꢀ, 2C), 69.1 (ꢀ, 2C), 69.9 (ꢀ, 2C), 70.1
(ꢀ, 2C),111.3 (þ,1C),112.3(þ, 2C),118.4 (þ,1C),123.4(Cquat,1C),125.1
(Cquat, 2C),126.2 (þ, 2C),127.2 (þ, 2C),128.9 (Cquat,1C),132.0 (þ,1C),
136.2 (Cquat, 1C), 149.7 (Cquat, 2C), 155.4 (Cquat, 1C), 168.0 (Cquat, 2C);
MS (ESI-MS, CH2Cl2/MeOHþ10 mmol NH4OAc): m/z (%)¼726.3 (23,
d
[ppm]¼28.0 (þ, 2C), 28.2 (þ, 1C), 44.7 (ꢀ, 1C), 52.5 (þ, 2C), 53.8
(ꢀ, 2C), 59.2 (ꢀ, 1C), 69.3 (ꢀ, 2C), 69.4 (ꢀ, 2C), 69.8 (ꢀ, 1C), 70.6 (ꢀ,
2C), 71.2 (ꢀ, 2C), 83.1 (Cquat, 1C), 110.4 (þ, 1C), 113.6 (þ, 1C), 114.1 (þ,
2C), 121.8 (þ, 1C), 125.3 (Cquat, 2C), 127.4 (þ, 2C), 129.3 (þ, 2C), 131.1
(Cquat, 1C), 139.0 (Cquat, 1C), 150.5 (Cquat, 2C), 153.3 (Cquat, 1C), 155.8
MHþ), 363.7 (100, (Mþ2Hþ)2þ); UV (MeOH):
l
(
3)¼298 (22,000), 220
(Cquat,1C),167.8 (Cquat, 2C),171.0 (Cquat,1C); IR (KBr):
n
(cmꢀ1)¼3319
(26,700); HRMS (FABMS glycerine): calcd for C36H48N5O1þ1
:
(br m), 2941 (m), 2873 (m), 1718 (m), 1614 (m), 1577 (m), 1407 (m),
1352 (s), 1287 (s), 1195 (m), 1125 (s), 1061 (m), 1027 (s), 980 (m), 911
(m), 846 (m), 780 (m), 731 (m); MS (ESI-MS, CH2Cl2/
MeOHþ10 mmol NH4OAc): m/z (%)¼826.3 (81, MHþ), 413.6 (100,
726.3350, found: 726.3346; MF: C36H51N5O11Cl2, FW: 800.74 g/mol.
4.5.2. 14-[4-[2-(Pyrene-1-carbonyl)-guanidino-methyl]-benzyl]-
6,7,9,10,13,14,15,16,18,19,21,22-dodecahydro-12H-5,8,11,17,20,23-hex-
aoxa-14-aza-benzocycloheneicosene-2,3-dicarboxylic acid dimethyl
ester hydrochloride (33). Compound 31 (96 mg, 0.10 mmol) was
deprotected according to GP VII to give the product 33 as a yellow
glass (76 mg, 0.088 mmol, 88%). 1H NMR (600 MHz, CDCl3):
(Mþ2Hþ)2þ); UV (MeOH):
l
(3)¼303 (22,900), 222 (27,500); HRMS
(PI-LSI-MS FAB Glycerine): calcd for C41H56N5Oþ13: 826.6870, found:
826.3866; MF: C41H55N5O13, FW: 825.92 g/mol.
4.4.2. 14-[4-[2-(tert-Butyloxycarbonyl)-3-(pyrene-1-carbonyl)-gua-
nidino-methyl]-benzyl]-6,7,9,10,13,14,15,16,18,19,21,22-dodecahydro-
12H-5,8,11,17,20,23-hexaoxa-14-aza-benzocycloheneicosene-2,3-di-
carboxylic acid dimethyl ester (31). Conversion of 4d (136 mg,
0.20 mmol) by GP VII yields a yellowglass (119 mg, 0.124 mmol, 62%).
Ethanol/ethyl acetate 1/9 was used for purification. 1H NMR
d
[ppm]¼3.21 (m, 4H), 3.61–3.68 (m, 8H), 3.81–3.96 (m, 8H), 3.86 (s,
6H), 4.09–4.14 (m, 4H), 4.51 (m, 2H), 4.63 (m, 2H), 6.93 (s, 2H), 7.11 (d,
2H, J¼4.6 Hz), 7.41 (d, 2H, J¼4.6 Hz), 7.97–8.11 (m, 3H), 8.13–8.21 (m,
2H), 8.22–8.28 (m, 2H), 8.36 (m, 1H), 8.71 (m, 1H), 10.23 (br s, 1H),
10.96 (br s, 1H), 13.51 (br s, 1H); 13C NMR (150 MHz, CDCl3):
d
[ppm]¼44.3 (ꢀ, 1C), 52.2 (ꢀ, 2C), 52.9 (þ, 2C), 56.8 (ꢀ, 1C), 65.6 (ꢀ,
(600 MHz, CDCl3):
d
[ppm]¼1.48 (s, 3H),1.52 (s, 6H),1.86(m, 2H), 2.71
2C), 68.2 (ꢀ, 2C), 69.2 (ꢀ, 2C), 70.0 (ꢀ, 2C), 70.2 (ꢀ, 2C),112.3 (þ, 2C),
123.9 (þ, 1C), 124.2 (Cquat, 1C), 124.3 (þ, 1C), 124.9 (Cquat, 2C), 125.2
(m, 4H), 3.59–3.61 (m, 8H), 3.62–3.71 (m, 4H), 3.72–3.93(m, 4H), 3.82
(s, 6H), 4.09–4.18 (m, 4H), 4.71 (d, 2H, J¼5.3 Hz), 7.09–7.18 (m, 2H),
7.25–7.32 (m, 4H), 8.68 (d, 1H, J¼4.6 Hz), 8.91 (br s, 1H), 9.30 (d, 1H,
(Cquat, 1C), 126.4 (þ, 1C), 126.5 (þ, 1C), 126.6 (Cquat, 1C), 126.9 (Cquat
,
,
1C),127.0(þ, 2C),127.4(þ,1C),129.9(þ,1C),130.2(þ,1C),130.6(Cquat
J¼4.6 Hz), 9.56 (br s, 1H); 13C NMR (150 MHz, CDCl3):
d
[ppm]¼28.1
1C), 130.7 (Cquat, 1C), 132.2 (þ, 5C), 134.7 (þ, 1C), 135.8 (þ, 1C), 131.3
(þ, 2C), 28.3 (þ, 1C), 44.8 (ꢀ, 1C), 52.5 (ꢀ, 1C), 52.6 (þ, 2C), 53.6 (ꢀ,
2C), 69.3–71.2 (ꢀ, 10C), 83.4 (Cquat, 1C), 114.0 (þ, 2C), 124.1 (þ, 1C),
124.6 (Cquat, 1C), 124.8 (þ, 1C), 125.0 (Cquat, 1C), 125.2 (þ, 1C), 125.2
(Cquat, 1C), 150.0 (Cquat, 2C), 155.8 (Cquat, 1C), 168.2 (Cquat, 2C), 172.2
(Cquat, 1C); IR (KBr):
n
(cmꢀ1)¼3302 (br m), 2916 (m), 2878 (m), 1675
(s),1596 (m),1515 (m),1436 (m),1351 (m),1267 (m),1197 (s),1129 (s),
1066 (m), 977 (m), 913 (m), 832 (m), 725 (m); MS (ESI-MS, CH2Cl2/
MeOHþ10 mmol NH4OAc): m/z (%)¼861.4 (21, MHþ), 431.8 (100,
(Cquat, 2C), 125.6 (þ, 1C), 125.7 (Cquat, 1C), 126.0 (þ, 1C), 126.4 (Cquat
,
1C),126.7 (Cquat,1C),127.1 (Cquat,1C),127.4 (þ,1C),127.7 (þ, 2C),127.9
(þ, 2C), 128.3 (þ, 1C), 128.4 (þ, 1C), 128.7 (þ, 1C), 130.3 (Cquat, 1C),
150.2 (Cquat, 2C), 153.3 (Cquat, 1C), 156.0 (Cquat, 1C), 163.9 (Cquat, 1C),
(Mþ2Hþ)2þ); UV (MeOH):
l
(3
)¼346 (22,500), 279 (35,000), 227
(68,700); HRMS (PI-LSI-MS FAB glycerine): calcd for C48H53N4O1þ1
861.3711, found: 861.3686; MF: C48H56N4O11Cl2, FW: 931.88 g/mol;
:
167.7 (Cquat, 2C), 180.9 (Cquat, 1C); IR (KBr):
n
(cmꢀ1)¼3312 (br m),
2943 (m), 2873 (m),1719 (m),1598 (m),1575 (m),1514 (m),1434 (m),
1398 (m),1346 (m),1287 (s),1193 (m),1125 (s),1050 (s), 982 (m), 911
(m), 847 (m), 808 (m), 730 (a), 646 (m); MS (ESI-MS, CH2Cl2/
MeOHþ10 mmol NH4OAc): m/z (%)¼960.1 (100, MHþ), 480.6 (100,
4.6. Example for the synthesis of receptors with the quaternary
ammonium motif via Huisgen-cycloaddition reaction
(Mþ2Hþ)2þ); UV (MeOH):
l
(3
)¼348 (35,600), 281 (42,100), 223
4.6.1. {4-[4-(2,3-Bis-methoxycarbonyl-6,7,9,10,12,13,15,16,18,19,21,22-
dodecahydro-5,8,11,17,20,23-hexaoxa-14-aza-benzocyclohenicosen-14-
ylmethyl)-2,3-dihydro-[1,2,3]triazol-1-yl]-phenyl}-trimethyl-ammo-
nium; iodide (21). Compound 19 (122 mg, 0.24 mmol) was
dissolved together with compound 20 (61 mg, 0.2 mmol) in 1.0 mL
of methanol. A solution of copper(II)sulfate pentahydrate (10 mg,
0.02 mmol) and sodium ascorbate (16 mg, 0.1 mmol) in water
(0.5 mL) was added drop wise. After stirring for 1 h at room tem-
perature, this solution was added again and the vigorously stirred
reaction mixture was heated 4 h to 60 ꢁC under nitrogen. After
cooling to room temperature, 9.0 mL dichloromethane were added,
the aqueous layer was separated off and the organic phase was
washed with 3.0 mL of brine. After drying the solution over MgSO4
the solvent was distilled off and the solid residue was purified on
(74,600); HRMS (PI-LSI-MS FAB glycerine): calcd for C53H61N4O1þ3
961.4235, found: 961.4263; MF: C53H60N4O13, FW: 961.09 g/mol.
:
4.5. Deprotection of aza-benzo-21-crown-7-ethers with
pyrrole- and pyrene substituted guanidine motifs (GP VIII)
The starting material (0.1 mmol) was dissolved in 2.0 mL of dry,
cold dichloromethane and a cold solution of HCl in diethylether
(1.0 mL) was added. After 4–6 h of stirring at room temperature
under moisture protection, all volatiles were removed at reduced
pressure. The residue was dissolved in a minimum amount of
dichloromethane and the product was precipitated carefully by
slow addition of diethylether. The solution was centrifuged, the