Cyclic Peptide–Polymer Complexes
FULL PAPER
Celite and solvent was removed under reduced pressure. The oily residue
was purified by flash chromatography on silica gel eluting with hex/
reaction mixture was purged with Ar for 5 min and heated at reflux for
12 h. The solvent was removed under reduced pressure and the resulting
oil was purified by flash chromatography on silica gel eluting with hex/
EtOAc (5:5 to 3:7) to give 10 as a yellow oil (3.78 g, 98%). R
f
=0.2
1
(
1
1
(
1:1hex/EtOAc); H NMR (300 MHz, CDCl
2.0 Hz), 2.26 ppm (s, 3H); C NMR (75 MHz, CDCl
3
): d=3.85 (d, 6H, J=
EtOAc (100:0 to 95:5) to afford 15 as a yellowish oil (1.68 g, 58%). R =
f
1
3
20
1
3
): d=189.7, 129.4,
0.1 (9:1 hex/EtOAc); [a]D =À6.9 (c=1.15, CHCl ); H NMR (300 MHz,
3
À1
26.2, 53.5, 27.0 ppm; IR (NaCl): n˜ =2960, 2127, 1660 cm ; MS: m/z
CDCl ): d=7.4–7.3 (m, 5H), 5.85–5.65 (m, 1H), 5.65–5.5 (m, 1H), 5.12
3
+
%): 192 (80) [M] , 109 (100); HRMS: m/z calcd for C
5
H
9
O
4
N
2
P:
(s, 2H), 4.40 (br, 0.33H, ABX), 4.26 (br, 0.66H, ABX), 4.01 (dd, 1H,
+
+
1
92.0300 [M] , found: 192.0304 [M] .
ABX, JAB =9.0 Hz, JAX =6.0 Hz), 3.73 (dd, 1H, ABX, JAB =9.0 Hz, J
BX
=
1
3
2
.0 Hz), 3.13 (d, 2H, J=7.0 Hz), 1.65–1.35 ppm (m, 15H); C NMR
Alkyne 11: Trichloroisocyanuric acid (1.02 g, 4.4 mmol) was added to a
solution of 7 (1.0 g, 4.3 mmol) in anhydrous CH Cl (7 mL). A solution of
TEMPO (6 mg, 0.04 mmol) in CH Cl (1 mL) was then added to the re-
sulting mixture at 08C. The reaction mixture was stirred for 30 min at
8C, filtered over silica eluting with hex/EtOAc (7:3), and the solvent
was removed under reduced pressure. EtOAc (15 mL) was added and the
organic layer was washed with a saturated aqueous solution of NaHCO
3ꢃ5 mL); it was dried (MgSO ) and removal of solvent under reduced
pressure gave 8 (991 mg, 100%) as a yellow oil.
CO (1.19 g, 8.6 mmol) was added to an ice-cooled solution of 8
991 mg, 4.3 mmol) and 10 (1.24 g, 6.5 mmol) in MeOH (15 mL). The re-
sulting solution was stirred for 1 h at 08C then for 16 h at RT. The mix-
ture was treated with a saturated aqueous solution of NH Cl (4 mL).
MeOH was removed under reduced pressure and H O (5 mL) was added
prior to extraction with EtOAc (3ꢃ10 mL). The combined organic ex-
tract was dried (MgSO ) and the solvent was removed under reduced
(
5
1
75 MHz, CDCl ): d=171.2, 151.9, 138.2, 128.6, 128.2, 123.7, 68.1, 66.5,
3
2
2
8.8, 37.6, 28.8 ppm; IR (NaCl): n˜ =3015, 2978, 1738, 1694, 1384,
2
2
À1
+
159 cm ; MS: m/z (%): 360 (5) [MÀCH
3
] , 260 (100); HRMS: m/z
+
+
calcd for C20
H
26
O
5
N: 360.1811 [MÀCH
3
] ; found: 360.1815 [MÀCH
3
] .
0
Acid 16: A 0.5m aqueous solution of NaOH (4.8 mL) was added to a so-
lution of 15 (596 mg, 1.6 mmol) in MeOH (8 mL). The reaction mixture
was stirred at RT for 16 h. MeOH was removed under reduced pressure,
H O (10 mL) was added, and the mixture was extracted with CH Cl (3ꢃ
3
(
4
2
2
2
1
0 mL). A 1m aqueous solution of HCl was added to the aqueous phase
until pH 4 was reached and it was extracted with EtOAc (4ꢃ15 mL). The
combined EtOAc extract was dried (MgSO ) and solvent was removed
K
(
2
3
4
under reduced pressure to afford 16 as a dark yellow solid (435 mg,
96%).
4
2
Pentafluorophenyl ester 17: A solution of DCC (267 mg, 1.3 mmol) in
EtOAc (2 mL) was added dropwise to a solution of acid 16 (351 mg,
1.2 mmol) and PfpOH (238 mg, 1.3 mmol) in EtOAc (6 mL). The result-
ing mixture was stirred at RT for 3 h. The white urea precipitate was fil-
tered off and the solvent was removed under reduced pressure. The oily
residue was purified was by flash chromatography on silica gel eluting
with hex/EtOAc (100:0 to 93:7) to yield 17 as a colorless oil (525 mg,
4
pressure. The residue was purified by flash chromatography on silica gel
eluting with hex/EtOAc (95:5) to give 11 as a colorless oil (652 mg,
2
D
0
1
6
(
4
7%). R
f
=0.3 (95:5 hex/EtOAc); [a] =À1 (c=1.25, CHCl
3
); H NMR
3
300 MHz, CDCl ): d =4.61 (br, 0.33H, ABX), 4.50 (br, 0.66H, ABX),
1
3
.1–4.0 (m, 2H), 2.27 (br, 1H), 1.7–1.45 ppm (m, 15H); C NMR
2
D
0
1
(
75 MHz, CDCl ): d=151.3, 94.4, 82.7, 80.3, 70.1, 68.7, 48.8, 28.4, 26.8,
3
95%). R =0.2 (93:7 hex/EtOAc); [a] =À17 (c=0.43, CHCl ); H NMR
f
3
2
1
5.8, 25.1, 24.3 ppm; IR (NaCl): n˜ =3260, 2980, 2360, 1703, 1378, 1263,
(300 MHz, CDCl ): d=5.85–5.65 (br, 2H), 4.45 (br, 0.33H, ABX), 4.32
3
À1
+
097 cm ; MS: m/z (%): 210 (45) [MÀCH
3
] , 110 (100); HRMS: m/z
(br, 0.66H, ABX), 4.05 (dd, 1H, ABX, JAB =9.0 Hz, JAX =6.0 Hz), 3.76
(d, 1H, ABX, J =9.0 Hz), 3.44 (d, 2H, J=5.0 Hz), 1.65–1.4 ppm (m,
15H); C NMR (75 MHz, CDCl ): d=167.3, 150.7, 142.8, 139.3, 134.9,
3
121.6, 120.1, 93.7, 79.8, 68.0, 58.6, 36.2, 28.3 ppm; IR (NaCl): n˜ =2981,
+
+
calcd for C11
H
16
O
3
N: 210.1130 [MÀCH
3
] ; found: 210.1133 [MÀCH
3
] .
AB
1
3
Alkene 12: A stream of Ar was passed though a solution of alkyne 11
497 mg, 2.2 mmol) and quinoline (64 mg, 0.5 mmol) in EtOH for 5 min.
A suspension of Lindlar catalyst (5%, 110 mg, 0.05 mmol) in EtOH
2 mL) was added. The mixture was purged with H (3ꢃ) and stirred for
6 h at RT. The precipitate was filtered off over Celite and the solvent
(
À1
+
1686, 1521, 1385, 1366 cm ; MS: m/z (%): 452 (10) [MÀCH
3
] , 413
+
(
2
(100); HRMS: m/z calcd for C20
H
23
F
5
O
5
N: 452.1496 [MÀCH
3
] ; found:
1
452.1486.
was removed under reduced pressure. The oily residue was purified by
flash chromatography on silica gel eluting with hex/EtOAc (100:0 to
Tripeptide 20: TFA (5 mL) was added to a suspension of 18 (817 mg,
2.6 mmol) in CH Cl (50 mL). The reaction mixture was stirred for 1 h at
2
2
9
3:7) to afford 12 as a colorless oil (433 mg, 86%). R
f
=0.3 (85:15 hex/
); H NMR (300 MHz, CDCl ):
d=5.80 (brm, 1H), 5.3–5.05 (m, 2H), 4.39 (br, 0.33H, ABX), 4.26 (br,
RT; it was then azeotroped with toluene (3ꢃ50 mL) to yield the TFA
salt 19 as an orange oil. This oil and 17 (1.16 g, 2.6 mmol) were dissolved
in MeAc (30 mL). A solution of K CO (889 mg, 6.4 mmol) in H O
2
0
1
EtOAc); [a] =+11.9 (c=1.04, CHCl
3
3
D
2
3
2
0
1
.66H, ABX), 4.04 (dd, 1H, ABX, JAB =9.0 Hz, JAX =6.0 Hz), 3.74 (dd,
H, ABX, JAB =9.0 Hz, JBX =2.0 Hz), 1.7–1.35 ppm (m, 15H); C NMR
(7 mL) was added and the reaction mixture was stirred at RT for 16 h.
The orange solution was concentrated under reduced pressure, poured
into H O, and extracted with CH Cl (3ꢃ15 mL). The aqueous phase was
acidified with a 1m aqueous solution of HCl until pH 4 was reached, then
it was extracted with EtOAc (4ꢃ15 mL). The combined EtOAc extract
1
3
(
75 MHz, CDCl
3
): d=159.1, 137.3, 115.7, 93.8, 80.1, 68.0, 59.6, 28.3,
2
2
2
À1
2
6.4 ppm; IR (NaCl): n˜ =2980, 1699, 1383, 1175 cm ; MS: m/z (%): 212
+
(
2
45) [MÀCH
3
] , 156 (100), 57 (100); HRMS: m/z calcd for C11
H
18
O
3
N:
+
+
12.1287 [MÀCH
3
] , found: 212.1290 [MÀCH
3
] .
was dried (MgSO
4
) and solvent was removed under reduced pressure.
Ester 14: A solution of benzyl chloroformate (7.02 g, 41.1 mmol) in anhy-
The resulting oil was purified was by flash chromatography on silica gel
drous CH
7.4 mmol) and pyridine (7.16 g, 90.5 mmol) in anhydrous CH
20 mL). The resulting mixture was stirred for 16 h at RT. The white pre-
cipitate was filtered off on Celite and the solution was washed with a sa-
turated aqueous CuSO (3ꢃ30 mL), dried (MgSO ), and the solvent was
removed under reduced pressure. The crude oil was purified by flash
chromatography on silica gel eluting with hex/Et O (100:0 to 95:5) to
afford 14 as a yellowish oil (4.77 mg, 72%). R =0.3 (9:1 hex/Et O); IR
H NMR (300 MHz,
): d=7.45–7.3 (m, 5H), 5.95 (m, 1H), 5.25–5.15 (m, 4H), 3.15 ppm
2
Cl
2
(30 mL) was added dropwise to a solution of 13 (3.22 g,
eluting with CH
2 2
Cl /MeOH (100:0 to 90:10) to give 20 as a viscous oil
1
3
(
2
Cl
2
(690 mg, 56%). R 0.15 (95:5 CH Cl /MeOH); H NMR (300 MHz,
f
2
2
CD
3
OD): d=8.15–7.9 (br, 2H), 5.8–5.55 (m, 6H), 4.30 (br, 1H), 4.05 (dd,
1H, J=9.0 Hz, J=6.0 Hz), 3.8–3.65 (m, 5H), 3.04 (d, J=7.0 Hz, 2H),
3.0–2.9 (m, 2H), 1.6–1.4 ppm (m, 15H); C NMR (75 MHz, CD OD):
3
d=174.0, 172.1, 132.4, 129.6, 129.1, 125.5, 125.2, 124.5, 93.6, 67.8, 59.0,
40.7, 40.6, 40.0, 36.9, 27.3 ppm; IR (NaCl): n˜ =3307, 2980, 2934, 2472,
1676, 1639, 1394 cm ; MS: m/z (%): 479 (%) [M] , 267 (100); HRMS:
+ +
1
3
4
4
2
À1
+
f
2
À1
1
(
NaCl): n˜ =3065, 3039, 2956, 1737, 1164 cm
;
m/z calcd for C24
Cyclopeptide 21: A solution of DIC (132 mg, 1.0 mmol) in EtOAc
5 mL) was added to a solution of acid 20 (477 mg, 0.99 mmol) and
37 7 3
H O N : 479.2631 [M] , found: 479.2622 [M] .
CDCl
3
1
3
(
1
d, 2H, J=7.0 Hz); C NMR (75 MHz, CDCl ): d=171.3, 135.9, 130.2,
3
(
+
28.6, 128.3, 118.7, 66.4, 39.1 ppm; MS: m/z (%): 176 (10) [M] , 91 (100);
+ +
PfpOH (192 mg, 1.0 mmol) in EtOAc (30 mL). The resulting mixture was
stirred at RT for 12 h. The white urea precipitate was filtered off and the
solvent was removed under reduced pressure. The residue was dissolved
in AcOH (5 mL). PTSA (1.8 mg, 0.01 mmol), Bz (5 mL), and a few drops
HRMS: m/z calcd for C11
12 2
H O : 176.0837 [M] ; found: 176.0831 [M] .
Alkene 15: The 2nd generation Grubbs catalyst (199 mg, 0.03 mmol) was
added to anhydrous CH Cl (0.8 mL) under an Ar atmosphere. The sus-
pension was purged with Ar for 2 min. Solutions of 12 (1.78 g, 7.8 mmol)
in anhydrous CH Cl (1.5 mL) and 14 (1.65 g, 9.4 mmol) in anhydrous
CH Cl (1.5 mL) were concomitantly added to the Grubbs catalyst. The
2
2
of H
was concentrated under reduced pressure to give an oil that was dis-
solved in CH Cl (5 mL) and TFA (5 mL). The mixture was stirred for
2
O were added. The mixture was stirred at RT for 12 h. The solution
2
2
2
2
2
2
Chem. Eur. J. 2009, 15, 4428 – 4436
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4435