The Journal of Organic Chemistry
Article
+
(
150 mL, three times). The combined organic layer was dried over
(MALDI-TOF) m/z 4088.7 ([M + H] ; expected mass for
+
anhydrous Na SO , filtered, concentrated under a vacuum, and
[C174H207F N O ] , 4088.3).
2
4
48
8
48
purified by column chromatography on silica gel (hexanes/EtOAc =
/1) to give tetrasubstituted benzene 6 as a yellow wax (15.1 g, 71%
Hexadeca Acid 10. Hexadeca acid 10 was prepared from
hexadeca-tert-butyl ester 9 by following the same procedure as used
5
1
yield). H NMR (400 MHz, CDCl ) δ 7.99 (s, 8H), 7.97 (s, 4H), 7.83
for the preparation of octa acid 7 and was obtained as a yellowish wax
3
13
1
(
s, 2H), 4.07 (s, 16H), 1.49 (s, 72H); C NMR (100 MHz, CDCl ) δ
in an 88% yield. H NMR (400 MHz, CDCl ) δ 8.14 (s, 8H), 8.12 (s,
3
3
1
9
1
9
66.0, 136.0, 133.4, 130.0, 128.4, 125.3, 124.8, 121.9 (q, J = 288.0 Hz),
3.6, 88.8, 83.0, 82.0−82.9 (m), 64.3, 28.0; F NMR (376 MHz,
4H), 8.08 (s, 2H), 4.55 (s, 16H), 4.32 (s, 16H), 4.26 (s, 16H);
F
19
NMR (376 MHz, CDCl ) δ −71.75; MS (MALDI-TOF) m/z 3212.2
3
+
+
CDCl ) δ −74.25; HRMS (ESI) calcd for C110H106F48NO24 ([M +
NH ] ) 2737.6372, found 2737.6361.
([M-H+Na] ; expected mass for [C H F N O Na] , 3212.3).
3
110 77 48 8 48
+
Amphiphile 11. Amphiphile 11 was prepared from hexadeca acid
10 by following the same procedure as used for the preparation of
4
Octa Acid 7. To a stirring solution of tetrasubstituted benzene 6
1
(
15.0 g, 5.5 mmol) and anisole (7.1 mL, 66.0 mmol) in CH Cl (100
amphiphile 1 and was obtained as a yellowish oil in a 58% yield. H
2
2
mL) was added trifluoroacetic acid (33.5 mL, 440.0 mmol). The
reaction mixture was stirred at room temperature for 4 h and then
concentrated under a vacuum. The residue was dissolved in NaOH (1
N, 40 mL) and extracted with CH Cl (20 mL, twice). The aqueous
NMR (400 MHz, CDCl ) δ 7.98 (s, 8H), 7.78 (s, 2H), 7.65 (s, 4H),
3
1
3
4.13 (s, 16H), 3.85 (s, 32H), 3.29−3.47 (m, 778H), 3.20 (s, 48H);
C
NMR (100 MHz, CDCl ) δ 168.8, 168.2, 166.6, 132.5, 128.9, 124.2,
3
121.7 (q, J = 290.0 Hz), 81.7−82.8 (m), 71.3, 69.9, 69.8, 69.6, 68.9,
2
2
layer was acidified by hydrochloric acid (1 N, 45 mL) to pH 3, and the
68.5, 64.6, 58.3, 52.7, 38.8, 29.0; 19F NMR (376 MHz, CDCl ) δ
3
+
precipitate was collected and dried under a vacuum to afford octa acid
−74.49; MS (MALDI-TOF) m/z 11868.2 ([M + NH ] ; expected
3
1
+
7
8
as a yellow wax (11.2 g, 90% yield). H NMR (400 MHz, CDCl ) δ
mass for [C
H
F N O ] , 11868.9).
3
510 897 48 25 224
19
9
.15 (s, 8H), 8.11 (s, 4H), 8.04 (s, 2H), 4.34 (s, 16H); F NMR (376
MHz, CDCl ) δ −71.97; MS (ESI) m/z 2270.7 ([M + H] ; expected
mass for [C H F O ] , 2271.1); HRMS (ESI) calcd for
Monomethylated PEG4 13. Under an atmosphere of argon,
sodium (5.5 g, 240.0 mmol) was slowly added to anhydrous MeOH
(100 mL), and the mixture was refluxed for 30 min. Then, a solution
of macrocyclic sulfate 12 (41.0 g, 160.0 mmol) in anhydrous MeOH
(40 mL) was slowly added, and the mixture was stirred at room
temperature for 12 h. Then, water (4.3 mL, 240.0 mmol) and H SO
+
3
+
7
8
39 48 24
+
C H F O Na ([M + Na] ) 2293.0884, found 2293.0845.
78
38 48 24
Amphiphile 1. Under an atmosphere of argon, DIC (4.0 mL, 26.4
mmol) was added to a stirring solution of HOBt (3.6 g, 26.4 mmol)
and octa acid 7 (5.0 g, 2.2 mmol) in DMF (100 mL) at 0 °C. After 20
min, amine 18 (14.8 g, 26.4 mmol) was added in one portion at room
temperature, and the reaction mixture was stirred at 45 °C for 12 h.
The reaction mixture was washed with brine (200 mL) and extracted
with CH Cl (150 mL, four times). The combined organic layer was
2
4
(6.5 mL, 120.0 mmol) were added, and the resulting mixture was
refluxed for 1 h. The reaction was quenched with saturated NaHCO3
solution (200 mL), and MeOH was removed under a vacuum. The
residue was extracted with CH Cl2 (100 mL, three times). The
2
combined organic layer was dried over anhydrous Na SO ,
2
2
2
4
dried over anhydrous Na SO , concentrated under a vacuum, and
concentrated under a vacuum, and purified by column chromatog-
2
4
purified by column chromatography on silica gel [CH Cl /methanol
raphy on silica gel (CH Cl /MeOH = 20/1) to give monomethylated
2
2
2
2
1
(
MeOH) = 10/1] to give amphiphile 1 as a yellow oil (11.3 g, 78%
PEG 13 as a clear oil (23.3 g, 70% yield). H NMR (400 MHz,
4
1
yield). H NMR (400 MHz, CDCl ) δ 7.97 (s, 2H), 7.93 (s, 4H), 7.82
CDCl ) δ 3.71−3.73 (m, 2H), 3.64−3.67 (m, 10H), 3.61−3.63 (m,
3
3
(
s, 8H), 4.03 (s, 16H), 3.63−3.66 (m, 352H), 3.54−3.56 (m, 32H),
2H), 3.56−3.57 (m, 2H,), 3.38 (s, 3H), 3.17 (s, 1H).
.38 (s, 24H); 13C NMR (100 MHz, CDCl ) δ 165.6, 132.8, 128.8,
Monomethylated PEG 14. Under an atmosphere of argon, a
9
3
1
7
3
8
27.4, 124.7, 124.6, 121.2 (q, J = 288.0 Hz), 92.9, 88.7, 81.5−82.6 (m),
solution of monomethylated PEG 13 (23.0 g, 110.5 mmol) in THF
4
19
1.4, 70.1, 70.0, 69.8, 69.0, 65.1, 58.4, 38.9, 29.1; F NMR (376 MHz,
(50 mL) was added dropwise into a suspension of NaH (4.0 g, 165.8
mmol) in THF (100 mL) at room temperature. After this mixture had
been stirred for an additional 30 min, a solution of macrocyclic sulfate
12 (42.5 g, 165.8 mmol) in THF (50 mL) was added, and the
resulting mixture was stirred at room temperature for an additional 12
h. Then, water (3.0 mL, 165.8 mmol) and H SO (4.5 mL, 82.9
+
CDCl ) δ −74.24; MS (MALDI-TOF) m/z 6627.9 ([M + HCN] ;
expected mass for [C2
3
+
H F N O ] , 6627.9).
79
447 48 9 112
Amphiphile 8. A suspension of amphiphile 1 (6.6 g, 1.0 mmol)
and palladium on carbon (0.7 g, 10 wt %) in methanol (50 mL) was
stirred under an atmosphere of hydrogen (4.0 MPa) at room
temperature for 12 h. Then, the mixture was filtered and concentrated
under a vacuum. The residue was purified by column chromatography
on silica gel (CH Cl /MeOH = 10/1) to give amphiphile 8 as a white
2
4
mmol) were added, and the resulting mixture was refluxed for 1 h. The
mixture was neutralized with saturated NaHCO solution (200 mL)
3
and extracted with CH Cl (150 mL, four times). The combined
2
2
2
2
1
oil (6.0 g, 90% yield). H NMR (400 MHz, CDCl ) δ 7.64 (s, 2H),
organic layer was dried over anhydrous Na SO , concentrated under a
3
2 4
7
3
.44 (s, 8H), 7.38 (s, 4H), 3.98 (s, 16H), 3.64−3.66 (m, 352H), 3.54−
vacuum, and purified by column chromatography on silica gel (CH Cl
2 2
.57 (m, 32H), 3.38 (s, 24H), 2.94 (s, 8H), 2.94 (s, 8H); 13C NMR
/MeOH = 20/1) to give monomethylated PEG 14 as a clear oil (39.5
8
1
(
100 MHz, CDCl ) δ 165.6, 143.4, 135.5, 129.9, 127.5, 125.4, 121.1
g, 93% yield). H NMR (400 MHz, CDCl ) δ 3.71−3.73 (m, 2H),
3.64−3.67 (m, 26H), 3.59−3.62 (m, 2H), 3.54−3.56 (m, 2H), 3.38 (s,
3
3
(
3
(
q, J = 288.0 Hz), 81.5−82.5 (m), 71.2, 69.8, 69.6, 69.0, 64.9, 58.2,
8.6, 36.4, 32.6, 27.2; 19F NMR (376 MHz, CDCl ) δ −74.27; MS
3H), 3.03 (s, 1H).
3
+
15
MALDI-TOF) m/z 6640.4 ([M + Na] ; expected mass for
Monomethylated PEG12 15. Monomethylated PEG12 15 was
+
[
C278H462F N O Na] , 6640.0).
prepared from monomethylated PEG8 14 by following the same
48
24 112
Hexadeca-tert-butyl Ester 9. Under an atmosphere of argon,
DIC (4.9 mL, 31.7 mmol) was added to a stirring solution of HOBt
4.3 g, 31.7 mmol) and octa acid 7 (6.0 g, 2.6 mmol) in DMF (100
mL) at 0 °C. After 20 min, di-tert-butyl 2,2′-azanediyldiacetate (7.8 g,
1.7 mmol) was added, and the mixture was stirred at 45 °C for an
procedure as used for the preparation of monomethylated PEG 14
and was obtained as a clear oil in a 90% yield. H NMR (400 MHz,
8
1
(
CDCl ) δ 3.71−3.73 (m, 4H), 3.63−3.67 (m, 40H), 3.59−3.62 (m,
3
2H), 3.54−3.56 (m, 2H), 3.38 (s, 3H), 2.80 (s, 1H).
1
5
3
Methylbenzenesulfonate 16. A solution of p-toluenesulfonyl
chloride (34.7 g, 182.0 mmol) in THF (50 mL) was slowly added to a
stirring solution of monomethylated PEG12 15 (51.0 g, 91.0 mmol)
and NaOH (8.8 N, 30 mL) in THF (150 mL) at 0 °C over 1 h, and
the resulting mixture was stirred at 45 °C for 4 h. Then, the reaction
mixture was diluted with brine (200 mL) and extracted with CH Cl
additional 12 h. The reaction mixture was washed with brine (200 mL)
and extracted with CH Cl (100 mL, three times). The combined
2
2
organic layer was dried over anhydrous Na SO , filtered, concentrated
2
4
under a vacuum, and purified by column chromatography (hexanes/
EtOAc = 4/1) to give hexadeca-tert-butyl ester 9 as a yellowish wax
2
2
1
(
8.8 g, 80% yield). H NMR (400 MHz, CDCl ) δ 7.97 (s, 4H), 7.93
(150 mL, three times). The combined organic layer was dried over
3
(
s, 10H), 4.30 (s, 16H), 4.07 (d, J = 8.0 Hz, 32H), 1.43 (d, J = 8.0 Hz,
anhydrous Na SO , concentrated under a vacuum, and purified by
2
4
1
1
2
44H); 13C NMR (100 MHz, CDCl ) δ 167.6, 166.4, 133.4, 129.5,
column chromatography on silica gel (CH Cl /MeOH = 20/1) to give
3
2 2
1
28.2, 125.1, 121.8 (q, J = 288.0 Hz), 93.3, 89.1, 82.9, 82.1, 65.4, 49.1,
methylbenzenesulfonate 16 as a clear oil (61.8 g, 95% yield). H NMR
8.0 (d, J = 150.0 Hz); 19F NMR (376 MHz, CDCl ) δ −73.94; MS
(400 MHz, CDCl ) δ 7.71 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz,
3
3
6
365
J. Org. Chem. 2015, 80, 6360−6366