Biomacromolecules
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ΔAbu), 167.77 (CO Trp); HRMS (ESI) m/z: [M]+ calcd for
Trp), 157.70 (C-6 Npx), 164.46 (CO ΔAbu), 169.79 (CO Trp),
174.82 (CO Npx); HRMS (ESI) m/z: [M + H]+ calcd for
+
C16H20N3O3 , 302.1499; found, 302.1500.
+
H-L-Trp-ΔAla-OMe,TFA (5c). Boc-L-Trp-ΔAla-OMe (4c) (0.13 g,
C30H32N3O5 , 514.2336; found, 514.2335.
0.34 mol) gave compound 5c as a yellow solid (66 mg, 51%); mp: deg
Npx-L-Trp-ΔAla-OMe (6c). H-L-Trp-ΔAla-OMe,TFA (5c) (0.40 g,
1.00 mmol) gave compound 6c from a column chromatography
(petroleum ether: ethyl ether, mixtures of crescent polarity) as a white
solid (0.15 g, 30%); mp: 145.0−147.0 °C; 1H NMR (400 MHz,
CDCl3, δ): 1.61 (d, J = 7.2 Hz, 3H, CH3), 3.09 (dd, J = 7.0 and 14.6
Hz, 1H, βCH), 3.29 (dd, J = 5.8 and 14.6 Hz, 1H, βCH), 3.70 (q, J =
7.2 Hz, 1H, CH), 3.71 (s, 3H, OCH3), 3.96 (s, 3H, OCH3 Npx),
4.71−4.78 (m, 1H, αCH), 5.83 (s, 1H, βCH), 5.98 (d, J = 7.2 Hz, 1H,
NH), 6.53 (s, 1H, βCH), 6.58 (s, 1H, 2-CH Trp), 7.03 (dt, J = 0.8 and
7.2 Hz, 1H, Ar H Trp), 7.13 (t, J = 2.4 Hz, 1H, Ar H Npx), 7.16−7.17
(m, 1H, Ar H Trp), 7.18 (dd, J = 2.8 and 8.8 Hz, 1H, Ar H Npx),
7.25−7.28 (m, 1H, Ar H Trp), 7.27−7.29 (m, 1H, Ar H Npx), 7.49 (d,
J = 8.0 Hz, 1H, Ar H Trp), 7.54 (d, J = 1.2 Hz, 1H, Ar H Npx), 7.63−
7.67 (m, 3H, 2 × Ar H Npx and NH), 8.02 (s, 1H, NH); 13C NMR
(100.6 MHz, CDCl3, δ): 18.12 (CH3), 27.32 (βCH2), 47.08 (CH),
52.77 (OCH3), 54.25 (αCH), 55.35 (OCH3 Npx), 105.57 (CH Npx),
109.20 (βCH2), 109.74 (3-C Trp), 111.07 (CH Trp), 118.71 (CH
Trp), 119.03 (CH Npx), 119.78 (CH Trp), 122.28 (CH Trp), 122.92
(2-CH Trp), 126.18 (CH Npx), 126.30 (CH Npx), 127.03 (3a-C
Trp), 127.59 (CH Npx), 129.01 (C Npx), 129.41 (CH Npx), 130.61
(αC), 133.78 (C Npx), 135.43 (2-C Npx), 136.07 (7a-C Trp), 157.77
(6-C Npx), 163.82 (CO ΔAla), 169.99 (CO Trp), 174.81 (C
1
> 140.0 °C; H NMR (300 MHz, DMSO-d6, δ): 3.13−3.28 (m, 2H,
βCH2), 3.75 (s, 3H, OCH3), 4.35 (brs, 1H, αCH), 5.84 (s, 1H, βCH),
6.22 (s, 1H, βCH), 6.98 (dt, J = 0.9 and 7.5 Hz, 1H, Ar H), 7.08 (dt, J
= 1.2 and 7.2 Hz, 1H, Ar H), 7.21 (d, J = 2.4 Hz, 1H, H-2 Trp), 7.36
(d, J = 7.4 Hz, 1H, Ar H), 7.62 (d, J = 8.1 Hz, 1H, Ar H), 8.19 (brs,
+
3H, NH3 ), 9.98 (s, 1H, NH), 11.03 (s, 1H, NH Trp); 13C NMR
(75.4 MHz, DMSO-d6, δ): 27.30 (βCH2), 52.76 (OCH3), 52.98
(αCH), 106.49 (C), 111.47 (CH), 111.63 (βCH), 118.45 (2 × CH),
121.18 (CH), 125.03 (CH), 127.04 (C), 136.26 (C), 132.03 (αC),
163.42 (CO ΔAla), 168.54 (CO Trp); HMRS (ESI) m/z: [M +
2+
H]2+ C15H18N3O3 requires 288.1343; found, 288.1342.
Synthesis of (S)-(+)-Naproxen Dehydrodipeptides (6a−c).
The methyl ester of the peptide (1.10 equiv) was dissolved in DCM (5
mL mmol−1) and put in an ice bath. Triethylamine (2.20 equiv) was
added and, slowly, (S)-(+)-naproxen chloride. The mixture was left
stirring at rt overnight (∼18 h). The mixture was filtered. Evaporation
at reduced pressure gave a residue that was partitioned between ethyl
acetate (50 mL) and KHSO4 (30 mL, 1 M). The organic phase was
thoroughly washed with KHSO4 (1 M), NaHCO3 (1 M), and brine (3
× 30 mL, each) and dried with MgSO4. Removal of the solvent
afforded compounds 6a−c.
+
Npx-L-Trp-Z-ΔPhe-OMe (6a). H-L-Trp-Z-ΔPhe-OMe,TFA (5a)
(0.30 g, 0.63 mmol) gave compound 6a from a column
chromatography (ethyl ether) as a white solid (0.14 g, 39%); mp:
211.0−213.0 °C; 1H NMR (400 MHz, DMSO-d6, δ): 1.26 (d, J = 7.2
Hz, 3H, CH3 Npx), 2.99 (dd, J = 9.0 and 14.4 Hz, 1H, βCH), 3.22
(dd, J = 5.2 and 14.4 Hz, 1H, βCH), 3.58 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3 Npx), 3.79−3.85 (m, 1H, CH Npx), 4.77−4.83 (m, 1H, αCH),
6.99 (dt, J = 0.8 and 7.2 Hz, 1H, Ar H Trp), 7.06−7.19 (m, 6H, βCH,
Ar H), 7.20 (d, J = 2.0 Hz, 1H, H-2 Trp), 7.23 (d, J = 2.8 Hz, 1H, Ar
H Npx), 7.35 (d, J = 8.4 Hz, 1H, Ar H Trp), 7.40 (dd, J = 1.6 and 8.8
Hz, 1H, Ar H Npx), 7.48 (d, J = 6.4 Hz, 1H, Ar H Npx), 7.66−7.70
(m, 5H, Ar H), 8.30 (d, J = 8.4 Hz, 1H, NH), 9.82 (s, 1H, NH), 10.85
(d, J = 1.6 Hz, 1H, NH); 13C NMR (100.6 MHz, DMSO-d6, δ): 18.85
(CH3 Npx), 27.68 (βCH2), 44.53 (CH Npx), 52.00 (OCH3), 53.17
(αCH), 55.09 (OCH3 Npx), 105.61 (CH Npx), 109.92 (C-3 Trp),
111.23 (CH Trp), 118.18 (CH Trp), 118.38 (CH), 118.54 (CH),
120.84 (CH), 123.72 (CH-2 Trp), 125.33 (CH Npx), 125.83 (C),
126.38 (CH ΔPhe), 126.61 (CH Npx), 127.36 (C-3a Trp), 128.31
(C), 128.37 (CH ΔPhe), 129.01 (CH ΔPhe), 129.19 (CH Npx),
129.92 (CH Npx), 131.89 (CH Npx), 133.04 (C), 133.10 (C), 136.05
(C-7a Trp), 137.26 (C-2 Npx), 156.88 (C-6 Npx), 165.33 (CO),
171.60 (CO Trp), 173.30 (CO Npx); HRMS (ESI) m/z: [M +
O Npx); HRMS (ESI) m/z: [M + H]+ calcd for C29H30N3O5 ,
500.2180; found, 500.2178.
Synthesis of the (S)-(+)-Naproxen N-Capped C-Deprotected
Dehydropeptides (7a−c). The (S)-(+)-naproxen-dehydrodipeptide
was dissolved in 1,4-dioxane (until 10 mL mmol‑1) and NaOH (1 M)
(1.5 equiv). The reaction was followed by TLC until no starting
material was detected. The organic solvent was removed under
reduced pressure, and the reaction mixture was acidified to pH 3 with
KHSO4 (1 M). The solid formed was filtered, affording compounds
7a−c.
Npx-L-Trp-Z-ΔPhe-OH (7a). Npx-L-Trp-Z-ΔPhe-OMe (6a) (0.14 g,
0.25 mmol) gave compound 7a as a white solid (0.13 g, 93%); mp:
199.0−200.0 °C; 1H NMR (400 MHz, DMSO-d6, δ): 1.23 (d, J = 7.2
Hz, 3H, CH3), 2.99 (dd, J = 9.6 and 14.4 Hz, 1H, βCH), 3.24 (dd, J =
4.4. and 14.4 Hz, 1H, βCH), 3.79 (q, J = 7.2 Hz, 1H, CH), 3.83 (s, 3H,
OCH3), 4.76−4.81 (m, 1H, αCH), 6.99 (dt, J = 0.8 and 7.2 Hz, 1H, Ar
H), 7.05−7.15 (m, 5H, Ar H), 7.20−7.25 (m, 3H, Ar H and βCH),
7.34−7.40 (m, 2H, Ar H), 7.49 (d, J = 6.4 Hz, 2H, Ar H), 7.64−7.70
(m, 4H, Ar H), 8.25 (d, J = 8.4 Hz, 1H, NH Trp), 9.65 (s, 1H, NH
ΔPhe), 10.83 (d, J = 1.6 Hz, 1H,1-NH Trp), 12.63 (brs, 1H, CO2H);
13C NMR (100.6 MHz, DMSO-d6, δ): 18.84 (CH3), 27.65 (βCH2),
44.60 (CH), 53.32 (αCH), 55.10 (OCH3), 105.61 (CH), 110.07 (C),
111.24 (CH), 118.16 (CH), 118.36 (CH), 118.56 (CH), 120.82
(CH), 123.76 (CH), 125.33 (CH), 126.40 (CH), 126.48 (C), 126.64
(CH), 127.41 (C), 128.28 (CH), 128.31 (C), 128.89 (CH), 129.05
(CH), 129.82 (CH), 131.56 (βCH), 133.02 (C), 133.59 (C), 136.06
(C), 137.22 (C), 156.88 (C), 166.27 (CO ΔPhe), 171.25 (CO
Trp), 173.31 (CO Npx); HRMS (ESI) m/z: [M + H]+ calcd for
+
H]+ calcd for C35H34N3O5 , 576.2493; found, 576.2498.
Npx-L-Trp-Z-ΔAbu-OMe (6b). H-L-Trp-Z-ΔAbu-OMe,TFA (5b)
(0.57 g, 1.37 mmol) gave compound 6b from a dry column
chromatography (petroleum ether/ethyl acetate, 1:1) as a white
1
solid (0.37 mg, 53%); mp: 180.0−182.0 °C; H NMR (400 MHz,
CDCl3, δ): 1.51 (d, J = 7.2 Hz, 3H, CH3 ΔAbu), 1.55 (d, J = 7.2 Hz,
3H, CH3 Npx), 3.22−3.24 (m, 2H, βCH2), 3.60 (s, 3H, OCH3 ΔAbu),
3.61 (q, J = 7.2 Hz, 1H, CH), 3.92 (s, 3H, OCH3 Npx), 4.86 (q, J = 7.2
Hz, 1H, αCH), 6.19 (d, J = 7.2 Hz, 1H, NH Trp), 6.67 (q, J = 7.2 Hz,
1H, βCH), 6.84 (d, J = 2.4 Hz, 1H, H-2 Trp), 7.07−7.08 (m, 1H, Ar H
Npx), 7.10 (dt, J = 0.8 and 8.0 Hz, 1H, H-5 Trp), 7.14 (dd, J = 2.8 and
8.8 Hz, 1H, Ar H Npx), 7.19 (dt, J = 1.2 and 8.0 Hz, 1H, CH-6 Trp),
7.22 (dd, J = 1.6 and 8.0 Hz, 1H, Ar H Npx), 7.31 (d, J = 8.0 Hz, 1H,
H-7 Trp), 7.35 (s, 1H, NH ΔAbu), 7.48 (d, J = 0.8 Hz, 1H, H-1 Npx),
7.58−7.61 (m, 2H, Ar H Npx), 7.62 (d, J = 7.6 Hz, 1H, CH-4 Trp),
8.02 (s, 1H, NH-1 Trp); 13C NMR (100.6 MHz, CDCl3, δ): 14.17
(CH3 ΔAbu), 17.99 (CH3 Npx), 27.12 (βCH2), 46.87 (CH), 52.12
(OCH3 ΔAbu), 53.76 (αCH), 55.30 (OCH3 Npx), 105.55 (CH Npx),
110.00 (C-3 Trp), 111.20 (CH-7 Trp), 118.66 (CH-4 Trp), 119.01
(CH Npx), 119.72 (CH-5 Trp), 122.18 (CH-6 Trp), 123.27 (CH-2
Trp), 125.83 (αC), 125.91 (CH Npx), 126.06 (CH-1 Npx), 127.35
(C-3a Trp), 127.49 (CH Npx), 128.91 (C Npx), 129.28 (CH Npx),
133.70 (C Npx), 134.40 (βCH), 135.65 (C-2 Npx), 136.11 (C-7a
+
C34H32N3O5 562.23365; found, 562.23306; [M + Na]+ calcd for
+
C34H31N3NaO5 , 584.2156; found, 584.2150.
Npx-L-Trp-Z-ΔAbu-OH (7b). Npx-L-Trp-Z-ΔAbu-OMe (6b) (0.37
g, 0.72 mmol) gave compound 7b as a cream solid (0.29 g, 81%); mp:
187.0−190.0 °C; 1H NMR (400 MHz, DMSO-d6, δ): 1.22 (d, J = 6.8
Hz, 3H, CH3 Npx), 1.43 (d, J = 6.8 Hz, 3H, CH3 ΔAbu), 2.98 (dd, J =
9.6 and 14.8 Hz, 1H, βCH), 3.19 (dd, J = 5.2 and 14.8 Hz, 1H, βCH),
3.78 (q, J = 6.8 Hz, 1H, CH), 3.84 (s, 3H, OCH3), 4.70−4.75 (m, 1H,
αCH), 6.49 (q, J = 6.8 Hz, 1H, βCH), 6.98 (dt, J = 0.6 and 7.3 Hz, 1H,
CH-5 Trp), 7.06 (dt, J = 1.0 and 7.5 Hz, 1H, CH-6 Trp), 7.10 (dd, J =
2.8 and 8.8 Hz, 1H, CH-7 Npx), 7.19 (d, J = 2.4 Hz, 1H, CH-2 Trp),
7.23 (d, J = 2.4 Hz, 1H, CH-5 Npx), 7.32 (d, J = 8.0 Hz, 1H, CH-7
Trp), 7.37 (dd, J = 1.6 and 8.4 Hz, 1H, CH-6 Npx), 7.64−7.72 (m,
4H, CH-4 Trp, CH-1 Npx, CH-4 Npx, CH-8 Npx), 8.21 (d, J = 8.4
Hz, 1H, αNH Trp), 9.14 (s, 1H, NH ΔAbu), 10.81 (d, J = 1.6 Hz, 1H,
NH-1 Trp), 12.42 (brs, 1H, CO2H); 13C NMR (100.6 MHz, DMSO-
d6, δ): 13.46 (CH3 ΔAbu), 18.49 (CH3 Npx), 28.09 (βCH2), 44.54
3566
Biomacromolecules 2015, 16, 3562−3573