10.1002/chem.202100523
Chemistry - A European Journal
FULL PAPER
Final Derivative 5. Synthetic protocol analogous to compound 3.
The title compound 5 was obtained as a colourless solid (12 mg,
Final Derivative 9. Synthetic protocol analogous to compound 8.
The title compound 9 was obtained as a colourless solid (2.3 mg,
15% over two steps). 1H NMR (400 MHz, [D6]DMSO): δ=11.56 (br. 2% over two steps). 1H NMR (500 MHz, [D6]DMSO): δ=11.54 (br
s., 1H), 11.20 (s, 1H), 10.56 (s, 1H), 9.69 (s, 1H), 8.98 (d, J =
7.5 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H),
7.87–8.01 (m, 5H), 7.76–7.84 (m, 3H), 7.63–7.72 (m, 3H), 7.60 (d,
J = 5.5 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H),
4.88–4.99 (m, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.78 (s, 3H), 3.20–
3.37 (m, 2H). 13C NMR (101 MHz, [D6]DMSO): δ=150.4 (Ar),
142.0 (Ar), 131.5 (Ar), 128.7 (Ar), 126.0 (Ar), 125.9 (Ar), 119.2
(Ar), 115.2 (Ar), 111.2 (Ar), 110.9 (Ar), 60.8 (OMe), 54.7 (OMe),
54.3 (α-C), 54.0 (OMe), 27.1 (β-C). HRMS (ESI): m/z calcd for
C43H36N8O11 [M+H]+ 841.2576; found 841.2584 (Δm = +1.0 ppm),
tR = 8.63 min.
s, 1H), 11.17 (s, 1H), 10.58 (s, 1H), 9.67 (s, 1H), 8.86–8.91 (m,
1H), 8.02–8.08 (m, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.93 (d, J =
8.1 Hz, 2H), 7.77–7.87 (m, 8H), 7.75 (d, J = 8.4 Hz, 2H), 7.69 (br
s, 1 H), 7.60–7.55 (m, 2H), 7.51 (d, J = 13.9 Hz, 2H), 4.90–4.97
(m, 1H), 3.91 (s, 3H), 3.77–3.79 (m, 3H), 3.77–3.79 (m, 3 H). 13
C
NMR (126 MHz, [D6]DMSO): δ=133.1, 131.2 (Ar-CH), 129.8 (CH-
Ar), 129.6 (Ar), 128.6 (Ar), 127.4 (Ar), 127.4 (Ar), 126.1 (Ar), 119.3
(Ar), 115.3 (Ar), 110.8 (Ar), 61.1 (OMe), 61.0 (OMe), 54.8 (α-C),
27.9 (β-C). HRMS (ESI): m/z calcd for C44H36N8O10 [M+H]+
837.2627; found 837.2631 (Δm = −0.4 ppm), tR = 8.87 min.
Final Derivative 10. Synthetic protocol analogous to compound
3. The title compound 9 was obtained as a colourless solid (4.0
mg, 2% over two steps). 1H NMR (400 MHz, [D6]DMSO): δ=11.52
(s, 1H), 11.16 (s, 1H), 10.49 (s, 1H), 9.65 (s, 1H), 9.01–9.22 (m,
1H), 8.68–8.75 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.93–8.00 (m,
2H), 7.73–7.82 (m, 5H), 7.63–7.70 (m, 1H), 7.54–7.63 (m, 2H),
7.29 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.65 (d, J =
8.3 Hz, 2H), 4.85–4.95 (m, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.06–
3.14 (m, 2H), 2.84–2.91 (m, 2H), 2.74–2.81 (m, 2H). 13C NMR
(101 MHz, [D6]DMSO): δ=129.8 (Ar), 129.4 (Ar), 119.2 (Ar), 127.9
(Ar), 128.8 (Ar), 115.6 (Ar), 60.5 (Ar), 60.9 (Ar), 46.1 (CH2), 37.4
(CH2), 36.1 (CH2). HRMS (ESI): m/z calcd for C43H39N7O11 [M+H]+
830.2780; found 830.2780 (Δm = 0 ppm), tR = 8.23 min.
Final Derivative 6. Synthetic protocol analogous to compound 3.
The title compound 6 was obtained as a colourless solid (25 mg,
32% over two steps). 1H NMR (400 MHz, [D6]DMSO): δ=11.55 (s,
1H), 11.19 (s, 1H), 10.56 (s, 1H), 9.69 (s, 1H), 8.98 (d, J = 7.5 Hz,
1H), 8.06 (d, J = 9.0 Hz, 1H), 7.96 (dd, J = 8.53, 15.6 Hz, 4H),
7.76–7.85 (m, 3H), 7.63–7.73 (m, 5H), 7.59 (dd, J = 5.4, 8.9 Hz,
2H), 7.30 (t, J = 8.9 Hz, 2H), 4.88–4.99 (m, 1H), 3.92 (s, 3H), 3.78
(s, 3H), 3.19–3.37 (m, 2H). 13C NMR (101 MHz, [D6]DMSO):
δ=134.2 (Ar), 132.7 (Ar),129.4 (Ar),128.1 (Ar), 126.1 (Ar), 125.8
(Ar), 119.1 (Ar), 116.5 (Ar), 115.3 (Ar), 110.6 (Ar), 60.8 (OMe),
60.6 (OMe), 54.7 (α-C), 27.6 (β -C). HRMS (ESI): m/z calcd for
C43H34FN7O10 [M+H]+ 828.2424; found 828.2427 (Δm =
+0.4 ppm) tR = 9.04 min.
Final Derivative 11. Synthetic protocol analogous to compound
8. The title compound 11 was obtained as a colourless solid (15
mg, 18% over two steps). 1H NMR (400 MHz, [D6]DMSO):
δ=11.54 (s, 1H), 11.19 (s, 1H), 10.55 (s, 1H), 10.54 (s, 1H), 9.69
(s, 1H), 8.76 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.98 (dd,
J = 6.7, 8.2 Hz, 4H), 7.85−7.94 (m, 4H), 7.76−7.84 (m, 3H),
7.62−7.72 (m, 3H), 7.59 (dd, J = 4.9, 8.9 Hz, 2H), 4.88−4.98 (m,
1H), 4.44 (s, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.18−3.38 (m, 2H).
(1H,13C)-HSQC NMR (400 MHz, [D6]DMSO): δ=132.1 (Ar), 129.0
(Ar), 128.7 (Ar), 125.9 (Ar), 126.0 (Ar), 119.7 (Ar), 119.2 (Ar),
115.0 (Ar), 110.6 (Ar), 83.7 (alkyne), 61.0 (OMe), 60.5 (OMe),
54.4 (α-C), 27.7 (β-C); HRMS (ESI): m/z calcd for C44H36N8O11
[M+H]+ 853.2576; found 853.2585 (Δm = +1.1 ppm), tR = 8.34 min.
Final Derivative 7. The tetrapeptide 43 (60 mg, 93 µmol, 1.0
equiv) and the active ester 33 (52 mg, 102 µmol, 1.1 equiv) were
dissolved in a mixture of anhyd. DMF (5 mL) and triethylamine
(0.10 mL, 744 µmol, 8.0 equiv). The mixture was stirred at room
temperature for 16 h. All volatiles were removed in vacuo and the
crude material was dissolved in DMSO and purified by HPLC
(PLRP-S, CH3CN in H2O). The title compound 7 (5.0 mg, 6%) was
obtained as a colourless powder. 1H NMR (400 MHz, [D6]DMSO):
δ=11.54 (s, 1H), 11.17 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H), 9.01
(d, J = 8.0 Hz, 1H), 7.77–7.83 (m, 5H), 7.73 (d, J = 8.5 Hz, 2H),
7.60 (d, J = 3.5 Hz, 1H), 7.57 (d, J = 3.8 Hz, 1H), 4.88–4.99 (m,
1H), 3.92 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, [D6]DMSO):
δ= 132.9 (Ar), 132.7 (Ar), 132.0 (Ar), 128.8 (Ar), 126.3 (Ar), 119.1
(Ar), 115.3 (Ar), 110.3 (Ar), 60.8 (OMe), 60.5 (OMe). HRMS (ESI):
m/z calcd for C44H34N8O10 [M+H]+ 835.2471; found 835.2469
(Δm = −0.2 ppm), tR = 9.38 min.
Final Derivative 12. To a solution of the alkyne derivative 11 (45
mg, 47 µmol, 1.0 equiv) and azidomethyl pivalate (5.1 µL, 47 µmol,
1.0 equiv) in a mixture of THF (2 mL) and H2O (2 mL) was added
CuSO4 · 5 H2O (0.58 mg, 2.3 µmol, 0.05 equiv). After purging the
solution with N2 for 5 min, sodium ascorbate (1.8 mg, 9.3 µmol,
0.20 equiv) was added and the reaction mixture was stirred at
room temperature for 16 h. MeOH (2 mL) and 3 N KOH(aq.) (2 mL)
were added and the solution was stirred for another 15 min at
room temperature. After adding 3 N HCl(aq.) (2.1 mL), the resulting
suspension was concentrated under reduced pressure. The crude
material was dissolved in DMSO, centrifuged, and the
supernatant was purified by HPLC (PLRP-S, CH3CN in H2O). The
title compound 12 (15 mg, 36% over two steps) was obtained as
a colourless powder. 1H NMR (400 MHz, [D6]DMSO): δ=11.55 (s,
1H), 11.19 (s, 1H), 10.57 (s, 1H), 10.53 (s, 1H), 9.69 (s, 1H), 8.77
Final Derivative 8. The tetrapeptide 42 (0.16 g, 0.22 mmol,
1.0 equiv) and the active ester 38 (0.11 g, 0.21 mmol, 1.0 equiv)
were dissolved in a mixture of anhyd. DMF (3 mL) and
triethylamine (0.29 mL, 2.1 mmol, 10 equiv). The mixture was
stirred at room temperature for 16 h. All volatiles were removed in
vacuo and the residue was taken up in a mixture of THF (2 mL)
and MeOH (2 mL), and 3 N KOH(aq.) (2 mL) was added dropwise
at 0°C. The ice bath was removed and after 15 min of stirring 3 N
HCl(aq.) (2.1 mL) was added and the resulting suspension was
concentrated under reduced pressure. The crude material was
dissolved in DMSO, centrifuged, and the supernatant was purified
by HPLC (PLRP-S, CH3CN in H2O). The title compound 8 (3.0 mg, (d, J = 7.3 Hz, 1H), 8.01−8.14 (m, 5H), 8.0 (d, J = 8.8 Hz, 2H),
2% over two steps) was obtained as a colourless powder. 1H NMR
(500 MHz, [D6]DMSO): δ=10.82 (br s, 1H), 10.59 (s, 1H), 9.61 (s,
1H), 8.79–8.84 (m, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.88 (d, J =
8.4 Hz, 2H), 7.80 (br d, J = 8.9 Hz, 3H), 7.66–7.70 (m, 1H), 7.60–
7.66 (m, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.41–7.51 (m, 3H), 7.28 (d,
J = 16.5 Hz, 1H), 7.07 (d, J = 16.5 Hz, 1H), 6.77–6.84 (m, 2H),
7.88−7.94 (m, 4H), 7.76−7.85 (m, 3H), 7.59 (dd, J = 3.76, 8.8 Hz,
2H), 4.93 (q, J = 7.7 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.19−3.38
(m, 2H). (1H,13C)-HSQC NMR (400 MHz, [D6]DMSO) δ=129.1 (Ar),
128.9 (Ar), 128.7 (Ar), 126.1 (Ar), 126.0 (Ar), 125.9 (Ar), 119.8
(Ar), 118.9 (Ar), 115.1 (Ar), 110.4 (Ar), 60.8 (OMe), 60.5 (OMe),
54.7 (α-C), 27.9 (β-C); HRMS (ESI): m/z calcd for C44H37N11O11
4.90–4.96 (m, 1H), 3.86 (s, 3 H), 3.79 (s, 3 H). 13C NMR (126 MHz, [M+H]+ 896.2747; found 896.2734 (Δm = −1.5 ppm), tR = 7.34 min.
[D6]DMSO): δ=130.7 (Ar-CH), 128.9, 128.4, 128.2, 125.9, 125.2,
Final Derivative 13. Synthetic protocol analogous to compound
125.0, 124.7 (CH-Ar), 124.4, 119.0 (Ar), 115.9 (Ar), 114.6 (Ar),
3. The title compound 15 was obtained as a colourless solid (18
107.8 (Ar), 60.6 (OMe), 59.8 (OMe), 54.6 (α-C), 27.5 (β-C). HRMS
mg, 14% over two steps). 1H NMR (400 MHz, [D6]DMSO):
(ESI): m/z calcd for C43H37N7O11 [M+H]+ 828.2624; found
δ=11.52 (s, 1H), 11.17 (s, 1H), 10.64 (s, 1H), 10.52 (s, 1H), 9.67
828.2628 (Δm = −0.4 ppm), tR = 8.11 min.
(s, 1H), 8.75 (d, J = 7.3 Hz, 1H), 8.16−8.25 (m, 4H), 8.06 (d, J =
9
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