K. Wang et al.
Bioorganic Chemistry 115 (2021) 105196
0 ◦C, N-hydroxy benzotrizol (HOBt, 2.7 mmol), diisopropylethylamine
(5.2 mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 4
mmol) were added. The mixture was stirred for 30 min before the
addition of aloperine (2.1 mmol), and was warmed to r.t. and stirred for
12 h. The mixture was washed with water and brine (30 mL), dried over
anhydrous Na2SO4, filtered and then the filtrate was concentrated in
vacuo. The residue was purified by flash column chromatography on
silica gel with CH2Cl2/CH3OH as the eluent to give the products 14a–r.
(m, 1H), 2.26 (s, 1H), 2.23–2.14 (m, 1H), 2.05–1.86 (m, 3H), 1.84–1.74
(m, 3H), 1.67–1.51 (m, 3H), 1.45–1.34 (m, 1H), 1.09–0.98 (m, 2H); 13C
NMR (151 MHz, CDCl3) δ 167.5, 146.6, 135.3, 132.1 (2), 128.6, 114.6
(2), 109.1, 59.5, 59.4, 54.5, 46.9, 45.4, 40.6, 35.2, 31.6, 28.1, 26.3,
24.9, 24.7, 24.1, 19.3. ESI-HRMS: calcd for C23H31BrN3O [M + H]+:
444.1645, found: 444.1651.
4.2.3.6. 12N-N′-p-Iodophenylaminoacetyl aloperine (14f). Yield 46%;
white solid; m.p. 85–87 ◦C. 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.4
Hz, 2H), 6.41 (d, J = 8.4 Hz, 2H), 5.64 (d, J = 5.4 Hz, 1H), 5.07–4.97 (m,
1H), 4.74 (d, J = 6.6 Hz, 1H), 3.94–3.88 (m, 1H), 3.82–3.70 (m, 2H),
3.44–3.36 (m, 1H), 3.07–3.02 (m, 1H), 2.78–2.71 (m, 2H), 2.62–2.56
(m, 1H), 2.44 (s, 1H), 2.37–2.31 (m, 1H), 2.29–2.22 (m, 1H), 2.19–2.07
(m, 1H), 2.00–1.95 (m, 1H), 1.94–1.73 (m, 5H), 1.72–1.62 (m, 2H),
1.49–1.38 (m, 1H), 1.15–1.03 (m, 2H); 13C NMR (151 MHz) δ 167.4,
147.2, 137.9 (3), 135.3, 128.6, 115.3 (2), 59.5, 59.4, 54.5, 46.9, 45.3,
40.6, 35.2, 31.6, 28.1, 26.3, 24.9, 24.7, 24.1, 19.3. ESI-HRMS: calcd for
4.2.3.1. 12N-N′-Phenylaminoacetyl aloperine (14a). Yield 58%; white
solid; m.p. 62–64 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.6 Hz,
2H), 6.72 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 5.65 (s, 1H), 4.95
(s, 1H), 4.76 (s, 1H), 4.06–3.90 (m, 1H), 3.91–3.80 (m, 1H), 3.79–3.65
(m, 1H), 3.49–3.38 (m, 1H), 3.12–2.98 (m, 1H), 2.75 (d, J = 6.8 Hz, 2H),
2.65–2.54 (m, 1H), 2.45 (s, 1H), 2.40–2.32 (m, 1H), 2.31–2.21 (m, 1H),
2.17–2.06 (m, 1H), 1.97 (s, 1H), 1.92–1.76 (m, 5H), 1.73–1.62 (m, 2H),
1.51–1.39 (m, 1H), 1.16–1.01 (m, 2H); 13C NMR (101 MHz) δ 167.9,
147.6, 135.5, 129.4 (2), 128. 4, 117.5, 113.1 (2), 59.4, 59.2, 54.4, 46.9,
45.5, 40.6, 35.1, 31.5, 28.0, 26.3, 24.9, 24.7, 24.1, 19.2. ESI-HRMS:
calcd for C23H32N3O [M + H]+: 366.2540, found: 366.2540.
C
23H31IN3O [M + H]+: 492.1506, found: 492.1517.
4.2.3.7. 12N-N′-p-Tolylaminoacetyl aloperine (14g).. Yield 48%; white
solid; m.p. 59–61 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.0 Hz,
2H), 6.56 (d, J = 8.4 Hz, 2H), 5.68–5.59 (m, 1H), 4.83–4.72 (m, 2H),
4.00–3.91 (m, 1H), 3.87–3.78 (m, 1H), 3.77–3.67 (m, 1H), 3.46–3.39
(m, 1H), 3.08–2.99 (m, 1H), 2.77–2.70 (m, 2H), 2.62–2.55 (m, 1H), 2.44
(s, 1H), 2.38–2.32 (m, 1H), 2.27–2.22 (m, 4H), 2.17–2.06 (m, 1H), 1.97
(s, 1H), 1.91–1.83 (m, 3H), 1.82–1.77 (m, 1H), 1.72–1.63 (m, 2H), 1.60
(s, 1H), 1.50–1.39 (m, 1H), 1.15–1.02 (m, 2H); 13C NMR (101 MHz) δ
168.1, 145.5, 135.5, 129.8 (2), 128.4, 126.7, 113.2 (2), 59.4, 59.2, 54.4,
46.9, 45.9, 40.6, 35.1, 31.5, 28.0, 26.3, 24.9, 24.7, 24.1, 20.5, 19.2. ESI-
HRMS: calcd for C24H34N3O [M + H]+: 380.2696, found: 380.2685.
4.2.3.2. 12N-N′-p-Fluorophenylaminoacetyl aloperine (14b). Yield 42%;
white solid; m.p. 64–66 ◦C. 1H NMR (600 MHz, CDCl3) δ 6.92–6.86 (m,
2H), 6.59–6.53 (m, 2H), 5.64 (d, J = 4.2 Hz, 1H), 4.82 (s, 1H), 4.75 (d, J
= 4.8 Hz, 1H), 3.97–3.89 (m, 1H), 3.84–3.77 (m, 1H), 3.77–3.67 (m,
1H), 3.47–3.30 (m, 1H), 3.11–3.01 (m, 1H), 2.79–2.70 (m, 2H),
2.63–2.54 (m, 1H), 2.44 (s, 1H), 2.39–2.32 (m, 1H), 2.30–2.21 (m, 1H),
2.16–2.07 (m, 1H), 2.05–1.95 (m, 1H), 1.94–1.73 (m, 5H), 1.72–1.60
(m, 2H), 1.49–1.39 (m, 1H), 1.15–1.02 (m, 2H); 13C NMR (151 MHz) δ
167.9, 156.0, 144.2, 135.4, 128.5, 115.9, 115.7, 113.9, 113.8, 59.5,
59.3, 54.5, 46.9, 46.2, 40.6, 35.2, 31.6, 28.1, 26.3, 24.9, 24.7, 24.2,
19.3. ESI-HRMS: calcd for C23H31FN3O [M + H]+: 384.2446, found:
384.2447.
4.2.3.8. 12N-N′-m-Trifluoromethylphenylaminoacetyl aloperine (14h)..
Yield 45%; white solid; m.p. 58–60 ◦C. 1H NMR (600 MHz, DMSO‑d6) δ
7.26 (d, J = 8.4 Hz, 1H), 6.98–6.87 (m, 2H), 6.83 (d, J = 7.8 Hz, 1H),
6.14 (t, J = 4.8 Hz, 1H), 5.60 (d, J = 5.4 Hz, 1H), 4.60–4.51 (m, 1H),
4.10–4.02 (m, 1H), 3.96–3.88 (m, 1H), 3.71–3.64 (m, 1H), 3.54–3.46
(m, 1H), 2.97–2.89 (m, 1H), 2.75–2.69 (m, 1H), 2.69–2.62 (m, 1H),
2.56–2.51 (m, 1H), 2.36–2.29 (m, 1H), 2.28–2.16 (m, 2H), 2.04–1.96
(m, 1H), 1.95–1.88 (m, 2H), 1.84–1.74 (m, 3H), 1.68–1.58 (m, 2H),
1.58–1.50 (m, 1H), 1.45–1.33 (m, 1H), 1.09–0.97 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 167.2, 147.7, 135.3, 131.7, 129.7, 128.6, 124.5,
116.6, 113.8, 108.5, 59.4 (2), 54.4, 46.9, 45.1, 40.6, 35.1, 31.5, 28.0,
26.3, 24.9, 24.7, 24.1, 19.2. ESI-HRMS: calcd for C24H31F3N3O [M +
H]+: 434.2414, found: 434.2403.
4.2.3.3. 12N-N′-m-Fluorophenylaminoacetyl aloperine (14c). Yield 40%;
white solid; m.p. 64–66 ◦C. 1H NMR (600 MHz, CDCl3) δ 7.13–7.06 (m,
1H), 6.43–6.35 (m, 2H), 6.31–6.24 (m, 1H), 5.65 (d, J = 5.4 Hz, 1H),
5.10 (s, 1H), 4.75 (d, J = 4.8 Hz, 1H), 3.99–3.90 (m, 1H), 3.84–3.78 (m,
1H), 3.78–3.71 (m, 1H), 3.46–3.32 (m, 1H), 3.12–3.01 (m, 1H),
2.79–2.70 (m, 2H), 2.64–2.56 (m, 1H), 2.45 (s, 1H), 2.38–2.32 (m, 1H),
2.31–2.22 (m, 1H), 2.20–2.07 (m, 1H), 2.00–1.95 (m, 1H), 1.95–1.81
(m, 4H), 1.81–1.73 (m, 1H), 1.72–1.62 (m, 2H), 1.50–1.38 (m, 1H),
1.15–1.03 (m, 2H); 13C NMR (151 MHz) δ 167.4, 164.3, 149.4, 135.3,
130.4, 128.6, 109.1, 103.9, 99.6, 59.5, 59.4, 54.5, 46.9, 45.4, 40.6, 35.2,
31.6, 28.1, 26.3, 24.9, 24.7, 24.1, 19.3. ESI-HRMS: calcd for
23H31FN3O [M + H]+: 384.2446, found: 384.2449.
4.2.3.9. 12N-N′-m-Methoxyphenylaminoacetyl aloperine (14i). Yield
50%; white solid; m.p. 60–62 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.09 (t, J
= 8.0 Hz, 1H), 6.27 (td, J = 8.0, 2.0 Hz, 2H), 6.17 (t, J = 2.0 Hz, 1H),
5.67–5.59 (m, 1H), 5.01–4.93 (m, 1H), 4.75 (d, J = 5.6 Hz, 1H),
3.99–3.91 (m, 1H), 3.86–3.79 (m, 1H), 3.78 (s, 3H), 3.76–3.68 (m, 1H),
3.45–3.37 (m, 1H), 3.08–3.01 (m, 1H), 2.77–2.71 (m, 2H), 2.62–2.56
(m, 1H), 2.47–2.40 (m, 1H), 2.39–2.32 (m, 1H), 2.31–2.22 (m, 1H),
2.16–2.06 (m, 1H), 2.00–1.94 (m, 1H), 1.93–1.83 (m, 3H), 1.82–1.65
C
4.2.3.4. 12N-N′-p-Chlorophenylaminoacetyl aloperine (14d). Yield 45%;
white solid; m.p. 73–75 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.8
Hz, 2H), 6.54 (d, J = 8.4 Hz, 2H), 5.64 (d, J = 4.0 Hz, 1H), 4.99 (s, 1H),
4.74 (d, J = 4.4 Hz, 1H), 4.02–3.86 (m, 1H), 3.84–3.65 (m, 2H),
3.46–3.31 (m, 1H), 3.12–2.98 (m, 1H), 2.74 (d, J = 7.6 Hz, 2H),
2.65–2.54 (m, 1H), 2.43 (s, 1H), 2.38–2.21 (m, 2H), 2.18–2.04 (m, 1H),
1.97 (s, 1H), 1.93–1.74 (m, 5H), 1.72–1.61 (m, 2H), 1.51–1.35 (m, 1H),
1.15–0.99 (m, 2H); 13C NMR (101 MHz) δ 167.5, 146.1, 135.3, 129.2
(2), 128.5, 122.0, 114.1 (2), 59.4, 59.3, 54.4, 46.9, 45.5, 40.6, 35.1,
31.5, 28.0, 26.3, 24.9, 24.6, 24.0, 19.2. ESI-HRMS: calcd for
C23H31ClN3O [M + H]+: 400.2150, found: 400.2152.
(m, 3H), 1.65–1.60 (m, 1H), 1.50–1.40 (m, 1H), 1.14–1.02 (m, 2H); 13
C
NMR (101 MHz) δ 167.7, 160.9, 149.0, 135.4, 130.1, 128.5, 106.3,
102.5, 99.1, 59.4, 59.2, 55.2, 54.4, 46.9, 45.5, 40.6, 35.1, 31.5, 28.0,
26.3, 24.9, 24.6, 24.1, 19.2. ESI-HRMS: calcd for C24H34N3O2 [M + H]+:
396.2646, found: 396.2634.
4.2.3.5. 12N-N′-p-Bromophenylaminoacetyl aloperine (14e). Yield 43%;
white solid; m.p. 73–75 ◦C. 1H NMR (600 MHz, DMSO‑d6) δ 7.22–7.17
(m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 5.79 (t, J = 4.8 Hz, 1H), 5.60 (d, J =
5.4 Hz, 1H), 4.54 (d, J = 5.4 Hz, 1H), 4.00–3.94 (m, 1H), 3.88–3.80 (m,
1H), 3.67–3.60 (m, 1H), 3.52–3.45 (m, 1H), 2.98–2.90 (m, 1H),
2.76–2.70 (m, 1H), 2.68–2.62 (m, 1H), 2.55–2.51 (m, 1H), 2.35–2.30
4.2.3.10. 12N-N′-p-Trifluoromethoxyphenylaminoacetyl aloperine (14j).
Yield 35%; white solid; m.p. 57–59 ◦C. 1H NMR (600 MHz, CDCl3) δ 7.04
(d, J = 8.4 Hz, 2H), 6.61–6.54 (m, 2H), 5.65 (d, J = 4.2 Hz, 1H), 5.03 (s,
1H), 4.75 (d, J = 4.2 Hz, 1H), 4.00–3.91 (m, 1H), 3.85–3.79 (m, 1H),
3.78–3.66 (m, 1H), 3.45–3.33 (m, 1H), 3.13–3.00 (m, 1H), 2.74 (d, J =
7.8 Hz, 2H), 2.64–2.56 (m, 1H), 2.44 (s, 1H), 2.38–2.31 (m, 1H),
9