The Journal of Organic Chemistry
Article
chromatography (AcOEt/EtOH/H O: 90/8/2) to give rise to
cryptophane 8 as a white solid (220 mg, 81%). H NMR (500
The solution was heated under reflux conditions for 60 h. TLC
2
1
(CHCl /Acetone: 7/3) was used to monitor the reaction. Then,
3
MHz, DMSO-d ): δ 8.56 (s, 1 H), 8.48 (s, 1 H), 8.43 (s, 1 H), 8.30 (s,
methanol (10 mL) was added to the solution. Evaporation of the
solvents gave rise to a dark brown solid. Water and CH Cl were
6
1
6
3
1
1
1
1
3
8
H), 8.14 (s, 1 H), 7.91 (s, 1 H), 6.77 (s, 1 H), 6.38 (s, 1 H), 6.69−
2
2
.63 (m, 8 H), 6.55 (m, 2 H), 5.32 (s, 1 H), 4.50−3.70 (m, 18 H),
added, and the product was extracted three times with CH Cl . The
2
2
.22 (m, 6 H). 13C NMR (125 MHz, DMSO-d ): δ 146.4, 146.35,
6
combined organic layers were washed with water and then with brine.
Then, the organic layer was washed with Na SO . Filtration and
45.7, 145.6, 145.5, 145.4, 145.3, 145.1, 144.5, 144.3 (2 C), 144.1,
33.9, 133.8, 133.6, 133.5, 133.3 (2 C), 131.1 (2 C), 130.5 (2 C),
29.5, 128.9, 120.2, 119.8, 119.0, 118.1 (2 C), 118.0, 117.6, 117.5,
17.4, 117.0, 116.9, 116.5. 71.5, 70.5, 69.2, 68.5 (3C), 68.2, 68.1, 35.1,
2
4
evaporation of the solvents under reduced pressure gave a yellow solid,
which was purified by column chromatography on silica gel (CHCl3/
Ethyl Acetate: 5/5). Evaporation of the solvents afforded a product,
+
4.9, 34.8. HRMS [M + H] calcd. for C H O : 841.2892; found,
49
45 13
which was then recrystallized in a CHCl /EtOH mixture. Compound
3
41.2855.
Method B (Purification): Synthesis of (rac)-anti-Crypto-
1
1
5 (151 mg, 71%) was collected on a frit. H NMR (500 MHz,
CDCl ): δ 6.94 (s, 1H), 6.85 (s, 1 H), 6.82 (s, 1H), 6.81 (s, 1H), 6.81
3
phane-13. Acetic anhydride (1.4 mL) was added in one portion to
a cooled solution of 8 (0.22 g, 0.26 mmol) in pyridine (5 mL). The
solution was then allowed to warm to room temperature and was
stirred for 4−5 h. The solution was then poured into a cooled mixture
of CH Cl /H O. The product was extracted three times with CH Cl .
(
(
s, 1 H), 6.80 (s, 1 H), 6.76 (s, 1 H), 6.72 (s, 1 H), 6.70 (s, 1 H), 6.67
s, 1 H), 6.63 (s, 1 H), 6.58 (s, 1 H), 6.54 (s, 1H), 5.08 (m, 1 H),
4
3
.80−4.40 (m, 29 H), 3.90 (m, 1 H), 3.85 (s, 6 H), 3.80 (s, 12 H),
13
.45−3.31 (m, 6H), 3.31 (s, 3 H). C NMR (126.7 MHz, CDCl , 25
3
2
2
2
2
2
The combined organic layers were then washed once with H O and
°C): δ 170.0, 169.9 (2 C), 169.8, 169.7, 169.3, 147.8 (3 C), 147.6,
147.5, 147.3, 147.2, 147.1, 147.0 (4 C), 134.7, 134.3, 133.9, 133.7,
133.6, 133.35 (2 C), 133.3, 133.2, 133.1, 133.0, 132.8, 121.4, 120.7,
120.6, 120.1, 120.05, 119.0, 118.9, 118.0, 117.3, 116.8, 116.4, 116.35,
81.4, 70.8, 69.8, 69.5, 69.05, 68.7, 68.5, 68.0, 67.6, 66.6 (3 C), 66.3,
52.15, 52.1 (2 C), 52.05, 52.0 (2 C), 38.8, 36.1 (3 C), 36.0 (2 C), 35.9.
2
dried over Na SO . Filtration followed by removal of the solvent under
2
4
reduced pressure left an oily residue, which was purified by
chromatography on silica gel. Purification on silica gel (CH Cl /
2
2
Acetone: 9/1) gave rise to compound 13 (0.22 g, 74%) as a white
1
glassy solid. H NMR (500 MHz, DMSO-d ): δ 7.13 (s, 1H), 7.09 (s,
6
+
2
1
4
H), 7.04 (s, 1H), 7.02 (s, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 6.96 (s,
H), 6.935 (s, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 4.89 (m, 1H), 4.65−
.55 (m, 6H), 4.30−3.95 (m, 12H), 3.45 (m, 6H), 2.39 (s, 3H), 2.34
HRMS (ESI) calcd for C H NaO S [M + Na ]: 1373.3717; found,
68
70
27
1
373.3760.
rac)-Cryptophane 1. A solution of KOH/H O (5.7 mL, 28.4
(
2
(
s, 3H), 2.29 (s, 6H), 2.28 (s, 3H), 2.24 (s, 3H), 0.18 (s, broad, 3H).
mmol; 0.5 M) was added in one portion to a stirred solution of 14
(120 mg, 0.094 mmol) in THF (5 mL). The mixture was heated at 60
1
3
C NMR (125 MHz, DMSO-d ): δ 170.2, 167.0 (4 C), 168.8 (2 C),
6
1
1
1
1
3
49.2 (2 C), 149.1, 149.0, 148.7, 148.4, 140.7 (2C), 140.6, 140.5,
39.4, 139.1, 138.5, 138.3, 138.2, 138.0, 137.5, 137.2, 133.85, 133.8,
33.7, 133.4, 132.4, 132.0, 125.0, 124.9, 124.5, 124.4, 124.0, 123.4,
20.8, 120.4, 120.2, 120.1, 114.7, 114.1, 70.8, 69.5, 69.2, 65.0, 64.5,
°
C for 18 h. The THF layer was then removed under reduced
pressure. Water (5 mL) was then added, and the solution was cooled
in an ice bath. The aqueous solution was then acidified with a few
drops of a concd HCl solution. The resulting precipitate was then
collected on a frit and washed three times with water. It was then dried
on the frit and finally washed several times with diethyl ether. Desired
6.6, 36.5, 36.2 (4 C), 21.0 (5 C), 20.8. HRMS (ESI) calcd for
+
C H O [M ]: 1135.3594; found, 1135.3625. Compound 8 was
63
58 20
recovered by hydrolysis under a basic solution. A solution of NaOH/
1
compound 1 was obtained as a white powder (95 mg; 85%). H NMR
H O (7 mL, 0.5 M) was added in one portion to a stirred solution of
2
(
500 MHz, DMSO-d ): δ 6.90 (s, 3 H), 6.88 (s, 1 H), 6.85 (s, 1 H),
6
1
3 (0.20 g, 0.17 mmol) in THF (7 mL). The mixture was stirred
6
4
.84 (s, 1 H), 6.83 (s, 1 H), 6.82 (s, 3 H), 6.80 (s, 1 H), 6.76 (s, 1 H),
.80−4.40 (m, 19 H), 4.40−3.70 (m, 12 H), 3.31 (m, 6 H). C NMR
overnight at 60 °C under an argon atmosphere for 16 h. The organic
layer was removed under reduced pressure, and 7 mL of water was
added to the solution. The solution was then cooled in an ice bath and
acidified with a few drops of a concd HCl solution. The white
precipitate was collected on a frit, washed several times with water, and
then dried on the frit. It was then washed several times with diethyl
ether to give rise to compound 8 (0.13 g, 88%) as a pale yellow
compound.
1
3
(126.7 MHz, DMSO-d , 25 °C): δ 170.9, 170.5 (5 C), 147.2 (5 C),
6
1
1
46.5 (3 C), 146.2, 146.0, 145.6 (2 C), 133.7, 133.5, 133.4, 133.3,
33.1, 133.0, 132.6 (2 C), 132.5 (2 C), 132.3 (2 C), 119.7, 119.4,
118.7 (2 C), 118.2, 118.0 (2 C), 117.0, 116.8, 116.5, 116.4, 116.2, 72.6,
70.8, 68.8, 68.0 (4 C), 66.6 (2 C), 66.1 (2 C), 65.8 (2 C), 34.9 (6 C).
+
HRMS (ESI) calcd for C61
H
O
57
25 [M + H ]: 1189.3183; found,
(
rac)-Cryptophane 14. Methylbromoacetate (67.5 μL, 0.71
1189.3221.
mmol) was added to a stirred mixture of 8 (50 mg, 0.06 mmol) and
potassium carbonate (99 mg, 0.71 mmol) in dry DMF (4 mL). The
mixture was stirred for 20 h at room temperature under an argon
atmosphere. The reaction was then quenched by the addition of water
and ethyl acetate (EtOAc). The aqueous layer was extracted twice with
EtOAc and then dried with sodium sulfate. Filtration followed by
evaporation of the solvent under reduced pressure gave rise to a white
(rac)-Cryptophane 2. To a stirred solution of 8 (60 mg, 0.070
mmol) and K CO (0.16 g, 0.84 mmol) in DMF (2 mL) was added
2
3
tosylate derivative 17 (0.44 g, 1.4 mmol) dissolved in DMF (2 mL).
This solution was heated at 60 °C for 16 h under an atmosphere of
argon. The solvent was evaporated, and the residue was redissolved in
7
/2/1 EtOAc/MeOH/H O and absorbed onto SiO . Purification by
2
2
flash chromatography on silica gel (EtOAc/MeOH/H O: 7/2/1)
2
solid. Purification by column chromatography (CHCl /Acetone: 7/3)
3
afforded the product as a colorless oil. Precipitation of PEG impurities
was achieved by dissolution in ether followed by filtration. Evaporation
1
gave desired compound 14 as a white solid (40 mg, 53%). H NMR
(
(
500 MHz, CDCl ): δ 6.81 (s, 1 H), 6.80 (s, 1 H), 6.78 (s, 1 H), 6.77
s, 1 H), 6.76 (s, 1 H), 6.73 (s, 1 H), 6.69 (s, 1 H), 6.67 (s, 3 H), 6.65
3
of the filtrate afforded the purified product as a colorless oil (0.10 g,
1
8
2%). H NMR (500 MHz, MeOD): δ 6.96−6.79 (12 H, m, ArH),
(
s, 2 H), 4.70−4.40 (m, 18 H), 4.40−3.90 (m, 13 H), 3.84 (s, 6 H),
1
3
13
4.67−4.57 (6 H, m), 4.49−3.57 (87 H, m), 3.44−3.31 (23 H, m). C
3
2
1
1
1
6
5
.81 (s, 12 H), 3.50−3.30 (m, 6 H). C NMR (126.7 MHz, CDCl ,
3
NMR (125 MHz, MeOD): δ 149.5, 149.4, 149.3, 149.2(8) (2 C),
5 °C): δ 170.0, 169.9 (2 C), 169.8, 169.7 (2 C), 147.7, 147.6 (2 C),
47.5, 147.4 (4 C), 147.3 (2 C), 147.1, 146.8, 134.5, 133.7, 133.5,
34.4 (2 C), 133.35, 133.3, 133.25, 133.2, 132.7, 132.5, 120.9, 120.8,
20.0 (2 C), 119.3 (2 C), 118.3, 118.0, 117.9, 117.5 (2 C), 115.9, 71.3,
9.4, 69.2, 68.7, 68.6, 68.3, 67.7 (3 C), 67.6, 67.2, 67.1 (2 C), 52.15,
1
1
1
1
7
49.2(1), 149.1(4), 149.1(1), 148.9, 148.4, 147.8, 147.7, 135.3(5),
33.3(3), 135.3, 135.2, 135.1, 135.0, 134.7 (2 C), 134.5(2 C),
34.3(3), 134.3(0), 121.1, 121.0, 120.9, 120.8, 120.6, 120.4, 120.2,
20.0, 119.6, 119.3, 118.2, 117.4, 73.1, 73.0, 72.9, 72.2, 71.9, 71.8(5),
1.8(0), 71.6, 71.5, 71.4, 71.3, 71.2, 70.5, 69.5, 69.4, 69.2, 59.2, 59.1,
2.1, 52.05 (2 C), 52.0 (2 C), 36.2 (2 C), 35.9 (4 C). HRMS (ESI)
+
calcd for C H O [M + H ]: 1273.4122; found, 1273.4111.
36.8, 36.7(4), 36.7(0), 36.6, 30.7 (32 magnetically equivalent carbons
67
69 25
+
(
rac)-Cryptophane 15. Mesyl chloride (364 μL) was added under
an argon atmosphere to a stirred mixture of cryptophane 14 (0.2 g,
.157 mmol) in a mixture CH Cl (10 mL) and pyridine (670 μL).
overlapping or obscured). MS (ESI) m/z: 1736 ([M + NH
HRMS (ESI, [M + 2H] ) calcd for C91
859.4277.
4
] , 100%).
H O31, 859.4293; found,
130
+
0
2
2
6
150
J. Org. Chem. 2015, 80, 6143−6151