Study on Peptides on Crown-Carriers
7.77 [d, J = 7.4 Hz, 1 H, ArH Fmoc], 7.68 [d, J = 7.4 Hz, 1 H,
ArH Fmoc], 7.53 [d, J = 7.4 Hz, 1 H, ArH Fmoc], 7.47–7.30 [m, 4
and CO Mdp], 156.4 [CO Fmoc], 148.1, 147.7 [CAr-O Mdp], 143.8,
143.6, 141.2, 129.9, 127.7, 127.1, 127.0, 124.9, 124.8, 123.6, 119.9,
H, ArH Fmoc], 7.26 [d, J ≈ 6.1 Hz, 1 H, NH Ala], 6.78 [d (partly 117.2, 113.3 [CAr Mdp and CAr Fmoc], 70.6, 70.53, 70.49, 70.44,
masked), J ≈ 7 Hz, 1 H, NH Ala], 6.77 [s, 1 H, NH Mdp], 6.75 [d
(partly masked), J ≈ 7 Hz, 1 H, NH Ala], 6.64 [d, J = 8.3 Hz, 1 H,
ArH5 Mdp], 6.59 [d (br), J ≈ 8 Hz, 1 H, ArH6 Mdp], 6.53 [s (br),
1 H, ArH2 Mdp], 6.49 [s (br), 1 H, ArH2 Mdp], 6.43 [d (br), J ≈
8.2 Hz, 1 H, ArH6 Mdp], 6.35 [d, J = 8.1 Hz, 1 H, ArH5 Mdp],
6.30 [s, 1 H, NH Mdp], 4.57 [dq, J ≈ 7.2 and 7.2 Hz, 1 H, CHα
Ala], 4.37 [dq, J ≈ 7.2 and 7.2 Hz, 1 H, CHα Ala], 4.32 [m (partly
masked), 1 H] and 4.15 [m (t-like), 1 H, OCH2 Fmoc], 3.93 [dq
(partly masked), 1 H, CHα Ala], 4.5–3.6 [m, 41 H, OCH2 and CH
Fmoc], 3.67 [s, 3 H, OCH3], 3.21 [m (br., q-like), J ≈ 7 Hz, 1 H,
CHα Ala], 3.56 [d (partly masked), 1 H] and 3.02 [d, J = 13.8 Hz,
70.39, 69.5, 69.4, 69.0, 68.8 [OCH2], 66.9 [CH2 Fmoc], 59.9 [Cα
Mdp], 57.2 [Cα Aib], 51.9 [OCH3], 50.8, 48.3 [CHα Ala], 46.9 [CH
β
β
β
Fmoc], 39.4 [ArCH2 Mdp], 26.5 [CH3 Mdp], 24.6, 23.7 [CH3
β
25
25
25
Aib], 17.1, 16.9 [CH3 Ala] ppm. [α] = –27, [α] = –28, [α]
=
589
578
546
25
–32, [α]
= –56 (c = 0.25, in MeOH). C46H60N4O13·0.5H2O
436
(885.980): calcd. C 62.35, H 6.94, N 6.32; found C 62.34, H 7.01,
N 6.03.
Boc-{Aib-L-Mdp[18-C-6]-L-Ala}2-OMe (6d): The peptide 4d
(0.133 g; 0.15 mmol) was N-deprotected in CH3CN (9 mL) and di-
ethylamine (1 mL) according to general procedure B. The crude
mixture of H--Ala-Aib--Mdp[18-C-6]--Ala-OMe and dibenzo-
fulvene was treated with the dipeptide Boc-Aib--Mdp[18-C-6]-
OH[35] (0.091 g; 0.15 mmol), HOAt (0.041 g; 0.30 mmol), NMM
(0.017 mL; 0.15 mmol) and EDC (0.044 g; 0.23 mmol) in CH2Cl2
(2 mL), at room temperature for 4 d under the same experimental
conditions and work-up procedure as for the synthesis of 3a. The
crude product was chromatographed on a 1.5 ϫ 29 cm column of
silica gel and eluted successively with eluants (V) and (VI). The
solution of the combined fractions containing the desired product
was treated by general procedure E to afford 0.075 g (40%) of pure
β
1 H, ArCH2 Mdp], 2.88 [d, J = 14.0 Hz, 1 H] and 2.73 [d, J =
β
β
14.0 Hz, 1 H, ArCH2 Mdp], 1.48 [s, 3 H, CH3 Mdp], 1.42 [s, 12
β
H, CH3 Mdp and CH3 Boc], 1.41 [d (partly masked), J ≈ 7.2 Hz,
3 H, CH3 Ala], 1.35 [d, J = 7.2 Hz, 3 H, CH3 Ala], 1.27 [d, J =
β
β
β
β
7.3 Hz, 3 H, CH3 Ala] ppm. 1.60 [s, 3 H, CH3 Mdp], 1.46 [d, J
β
β
= 7.2 Hz, 3 H, CH3 Ala], 1.42 [d, J = 7.3 Hz, 3 H, CH3 Ala],
β
1.34 [d (partly masked), J ≈ 7 Hz, 3 H, CH3 Ala], 1.33 [s, 3 H,
CH3 Mdp], 1.17 [d, J = 7.3 Hz, 3 H, CH3 Ala]. 13C NMR
(CDCl3): δ = 174.8, 174.1, 173.6, 172.8, 172.4, 172.0 [4 CO Ala and
2 CO Mdp], 157.7 [CO Fmoc], 148.9, 148.3, 147.6, 147.0 [CAr-O
Mdp], 143.9, 142.9, 141.2, 130.1, 128.0, 127.3, 127.2, 125.0, 124.5,
123.4, 121.7, 120.1, 115.7, 115.2, 113.6, 112.1 [CAr Mdp and CAr
Fmoc], 70.6, 70.5, 70.4, 70.3, 70.2, 70.1, 69.9, 69.5, 69.3, 69.2, 69.1,
68.8, 68.1 [OCH2], 66.9 [CH2 Fmoc], 59.8, 59.4 [Cα Mdp], 53.8 [CH
Fmoc], 51.9 [OCH3], 50.0, 48.9, 48.1, 46.7 [CHα Ala], 45.1, 38.4
β
β
1
hexapeptide 6d as a solid. Rf = 0.55 (VI). H NMR (CDCl3): δ =
7.73 [d, J = 7.0 Hz, 1 H, NH Ala], 7.68 [d (br) (partly masked), 1
H, NH Ala], 7.65 [s, 1 H, NH Aib], 6.79 [d, J = 7.9 Hz, 1 H, ArH
Mdp], 6.68–6.56 [m, 6 H, 5ArH Mdp and 1NH Mdp], 6.19 [s (br),
1 H, NH Mdp], 5.38 [s, 1 H, NH Aib], 4.53 [dq, J ≈ 7.2 and 7.2 Hz,
1 H, CHα Ala], 4.25 [dq (br), J ≈ 7.2 and 7.2 Hz, 1 H, CHα Ala],
4.15–3.65 [m, 40 H, OCH2], 3.69 [s, 3 H, OCH3], 3.56 [d, J =
[ArCH2β Mdp], 24.9, 22.5 [CH3β Mdp], 17.3, 17.1, 16.7, 15.7 [CH3
β
25
25
25
25
Ala] ppm. [α] = –66, [α] = –69, [α] = –81, [α] = –154 (c
β
589
578
546
436
14.0 Hz, 1 H] and 3.08 [d, J = 14.0 Hz, 1 H, ArCH2 Mdp], 2.94
= 0.10, in MeOH). ESI+ MS: m/z (%) = 1107 (100) [M – Fmoc +
H]+. C68H92N6O21·H2O (1347.480): C 60.61, H 7.03, N 6.24; found
C 60.68, H 6.74, N 5.96.
[d, J = 14.0 Hz, 1 H] and 2.77 [d, J = 14.0 Hz, 1 H, ArCH2β Mdp],
β
1.53 [s, 3 H, CH3 Mdp], 1.48 [d (partly masked), J ≈ 7.3 Hz, 3 H,
β
β
CH3 Ala], 1.36 [d (partly masked), J ≈ 7.3 Hz, 3 H, CH3 Ala],
1.48 [s, 3 H], 1.46 [s, 3 H], 1.29 [s, 3 H], 1.27 [s, 3 H] and 1.09 [s, 3
Fmoc-L-Ala-Aib-L-Mdp[18-C-6]-L-Ala-OMe (4d): The peptide
β
β
H, CH3 Mdp and 4CH3 Aib], 1.33 [s, 9 H, CH3 Boc] ppm. 13C
NMR (CDCl3): δ = 174.6, 174.2, 173.8, 173.4, 173.30, 173.31 [CO
Aib, Mdp and Ala], 155.9 [CO Boc], 148.8, 148.3, 147.9, 147.5
[CAr-O Mdp], 130.3, 127.8, 123.7, 122.8, 117.3, 115.8, 113.7, 113.3
[CAr Mdp], 81.3 [O-C Boc], 70.7, 70.6, 70.5, 70.4, 69.5, 69.4, 68.95,
68.91, 68.8 [OCH2], 59.4, 59.3 [Cα Mdp], 57.3, 56.9 [Cα Aib], 51.8
[OCH3], 49.8, 48.4 [CHα Ala], 43.4, 38.7 [ArCH2β Mdp], 28.2 [CH3
3d[35] (0.166 g; 0.24 mmol) was N-deprotected in CH2Cl2 (7.5 mL)
and TFA (2.5 mL) according to general procedure A. The crude
TFA·H-Aib--Mdp[18-C-6]--Ala-OMe (not characterized) was
treated with Fmoc--Ala-NCA (0.246 g; 0.73 mmol) and DIEA
(0.127 mL; 0.73 mmol) in THF (2 mL) at room temperature for
5 d. The same work-up as for 3a was applied. The crude product
was chromatographed on a preparative TLC plate of silica gel with
eluant (V). The separated band in the silica gel containing the de-
sired product was extracted with several portions of eluant (IV)
and the filtered solution was treated by general procedure E to
afford 0.155 g (73%) of pure 4d as a solid. Rf = 0.67 (IV), 0.33 (V).
1H NMR (CDCl3): δ = 7.74 [d, J = 7.5 Hz, 2 H, ArH Fmoc], 7.57
[d (br), J ≈ 7.4 Hz, 1 H, ArH Fmoc], 7.56 [d (br), J ≈ 7.5 Hz, 1 H,
ArH Fmoc], 7.49 [d, J = 7.0 Hz, 1 H, NH Ala], 7.38 [m (t-like), J
β
β
Boc], 26.6, 26.1, 24.8, 23.6, 23.4, 22.4 [CH3 Mdp and CH3 Aib],
β
25
25
25
17.0, 16.5 [CH3 Ala] ppm. [α] = –48, [α] = –49, [α] = –58,
589
578
546
[α]
= –104 (c = 0.24, in MeOH). ESI+ MS: m/z (%) = 1235.8
25
436
(100) [M + H]+, 1257.7 (100) [M + Na]+. C60H94N6O21 (1235.400):
calcd. C 58.33, H 7.67, N 6.80; found C 58.23, H 7.88, N 6.31.
Boc-Aib-
L-Mdp[benzo-24-C-8]-OH: The amino acid derivative Boc-
-Mdp[benzo-24-C-8]-OH[35] (1.087 g; 1.67 mmol) was N-depro-
≈ 7.3 Hz, 2 H, ArH Fmoc], 7.31–7.24 [m (partly masked), 2 H, tected in CH2Cl2 (15 mL) and TFA (5 mL) according to general
ArH Fmoc], 6.80 [s, 1 H, NH Mdp], 6.69 [d, J = 8.1 Hz, 1 H, ArH5
Mdp], 6.64 [d, J ≈1.6 Hz, 1 H, ArH2 Mdp], 6.61 [dd, J = 8.1 and
ca. 1.6 Hz, 1 H, ArH6 Mdp], 6.42 [s, 1 H, NH Aib], 5.79 [d, J =
6.5 Hz, 1 H, NH Ala], 4.53 [dq, J ≈ 7.1 and 7.1 Hz, 1 H, CHα Ala],
4.41 [dd (br), J ≈ 10.5 and 6.7 Hz, 1 H] and 4.35 [dd, J = 10.5 and
6.7 Hz, 1 H, OCH2 Fmoc], 4.17 [m (t-like), J ≈ 6.6 Hz, 1 H, CH
Fmoc], 4.05 [m, 4 H, OCH2], 3.95 [dq (br), J ≈ 6.8 and 6.8 Hz, 1
H, CHα Ala], 3.83 [m, 4 H, OCH2], 3.7–3.6 [s, 12 H, OCH2], 3.63
[s, 3 H, OCH3], 3.59 [d (partly masked), 1 H] and 3.00 [d, J =
procedure A. The crude TFA·H--Mdp[benzo-24-C-8]-OH (not
characterized) was treated with Boc-Aib-NCA (1.152 g; 5.02 mmol)
and DIEA (1.170 mL; 6.70 mmol) in THF (10 mL) at 50–55 °C for
2 d. The solvent was evaporated in vacuo and the residue was dis-
solved in CH2Cl2 (150 mL). The solution was washed with 0.5
HCl (2ϫ100 mL), H2O (2ϫ100 mL), dried (MgSO4), filtered, and
evaporated in vacuo. The crude product was chromatographed on
a 3ϫ50 cm column of silica gel with eluant (III) and then (IV).
The combined solution of the product-containing fractions was
treated by general procedure D to afford 0.617 g (50%) of pure
Boc-Aib--Mdp[15-C-5]-OH as a solid. Rf = 0.60 (IV), 0.58 (V).
β
β
14.0 Hz, 1 H, ArCH2 Mdp], 1.46 [s, 3 H, CH3 Mdp], 1.43 [d
(partly masked), J ≈ 7.2 Hz, 3 H, CH3β Ala], 1.42 [s, 3 H] and 1.32
β
β
[s, 3 H, CH3 Aib], 1.26 [d, J = 7.2 Hz, 3 H, CH3 Ala] ppm. 13C 1H NMR (CDCl3): δ = 7.64 [s, 1 H, NH Mdp], 6.93 [s (br), 5 H,
NMR (CDCl3): δ = 173.9, 173.6, 173.1, 172.7 [2 CO Ala, CO Aib
4ArH benzo and ArH2 Mdp], 6.72 [d (br), J ≈ 7.9 Hz, 1 H, ArH
Eur. J. Org. Chem. 2008, 1224–1241
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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