X. Yang, B. Cheng, Y. Xiao et al.
European Journal of Medicinal Chemistry xxx (xxxx) xxx
2H), 5.33 (s, 1H), 4.81 (s, 2H), 4.48 (s, 1H), 3.74 (s, 3H), 3.70 (s, 2H),
6.65 (s, 1H), 6.56 (s, 2H), 6.49 (m, 2H), 5.33 (s, 1H), 4.84 (s, 2H), 3.93
3.63 (s, 9H), 3.46 (m, 2H), 2.56 (t, J ¼ 5.8 Hz, 2H); 13C NMR (101 MHz,
(m, 1H), 3.85 (d, J ¼ 6.7 Hz, 1H), 3.75 (s, 3H), 3.65 (m, 9H), 3.52 (s,
DMSO)
d
153.17, 148.90, 148.24, 147.62, 133.01, 132.99, 130.33,
2H), 1.09 (d, J ¼ 6.3 Hz, 3H);13C NMR (101 MHz, DMSO)
d 176.55,
130.07, 129.83, 129.57, 128.97, 128.40, 127.96, 114.20, 112.26, 106.34,
153.17, 147.45, 146.37, 130.00, 129.80, 129.50, 128.35, 127.57, 106.36,
106.36, 99.82, 72.49, 72.02, 70.64, 61.69, 56.09, 55.97, 22.24; HRMS
m/z calcd for C30H36O8N 538.2435, found 538.2435 [M þ Hþ]; HPLC:
tR 15.352 min, purity 96.274%.
70.14, 60.64, 60.40, 56.08, 55.96, 52.96, 51.23; HRMS m/z calcd for
C
28H34O6N 480.2381, found 480.2387 [M
þ
Hþ]; HPLC: tR
15.180 min, purity 95.576%.
(Z)-2-((4-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)
methyl)benzyl)amino)-2-methylpropanoic acid (TP4). The title
compound was obtained as white solid (5.6 mg, 18% yield); mp:
(2R,4R)-4-hydroxy-1-(4-((2-methoxy-5-((Z)-3,4,5-
trimethoxystyryl)phenoxy)methyl)benzyl)pyrrolidine-2-
carboxylic acid (TP9). The title compound was obtained as white
solid (3.2 mg, 15% yield); mp: 140.9e142.1 ꢁC; 1H NMR (400 MHz,
200.5e201.3 ꢁC; 1H NMR (400 MHz, DMSO)
d
7.44 (d, J ¼ 8.0 Hz,
2H), 7.31 (d, J ¼ 8.0 Hz, 2H), 6.92 (dd, J ¼ 4.9, 3.3 Hz, 2H), 6.87 (dd,
J ¼ 8.5, 1.4 Hz, 1H), 6.56 (s, 2H), 6.47 (d, J ¼ 2.3 Hz, 2H), 5.33 (s, 1H),
4.86 (s, 2H), 3.89 (s, 2H), 3.75 (s, 3H), 3.63 (s, 9H), 1.33 (s, 6H); 13C
DMSO)
d
7.31 (dd, J ¼ 20.1, 7.1 Hz, 4H), 7.19 (s,1H), 6.92 (d, J ¼ 8.2 Hz,
2H), 6.87 (dd, J ¼ 8.3, 1.4 Hz, 1H), 6.56 (s, 2H), 6.48 (q, J ¼ 11.8 Hz,
2H), 5.33 (s, 1H), 4.83 (s, 2H), 4.18 (s, 1H), 4.02 (d, J ¼ 11.9 Hz, 1H),
3.75 (s, 3H), 3.63 (s, 9H), 3.52 (s, 2H), 1.99 (s, 2H), 1.46 (dd, J ¼ 7.5,
NMR (101 MHz, DMSO)
d 188.00, 170.82, 152.91, 148.79, 147.12,
144.23,136.80, 135.84,133.04, 130.08, 129.70,129.62, 129.07, 127.78,
122.96, 114.25, 112.34, 106.15, 69.67, 60.55, 57.05, 55.96, 24.37;
5.0 Hz, 2H); 13C NMR (101 MHz, DMSO)
d 171.46, 159.96, 159.39,
158.59, 152.91, 147.12, 144.23, 136.80, 135.84, 133.05, 130.09, 129.71,
129.07, 127.78, 122.97, 114.25, 112.34, 106.15, 69.67, 68.84, 60.55,
59.65, 55.96, 52.61, 37.41; HRMS m/z calcd for C31H36O8N 550.2435,
found 550.2432 [M þ Hþ]; HPLC: tR 15.080 min, purity 95.268%.
(Z)-(4-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)
HRMS m/z calcd for
C30H36O7N 522.2486, found 522.2482
[M þ Hþ]; HPLC: tR 15.567 min, purity 95.020%.
(Z)-4-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)methyl)
benzaldehyde (TP5). The title compound was obtained as yellow oil
(500 mg, 60% yield); 1H NMR (400 MHz, DMSO)
d
10.00 (s, 1H), 7.89
methyl)phenyl)methanol (TP10). The title compound was obtained
(d, J ¼ 8.0 Hz, 2H), 7.52 (d, J ¼ 8.0 Hz, 2H), 6.94 (d, J ¼ 8.2 Hz, 1H),
6.88 (dd, J ¼ 10.1,1.8 Hz, 2H), 6.53 (s, 2H), 6.50e6.43 (m, 2H), 5.01 (s,
2H), 3.77 (s, 3H), 3.62 (d, J ¼ 14.0 Hz, 9H); 13C NMR (101 MHz,
as white solid (6 mg, 23% yield); mp: 60.2e61.3 ꢁC; 1H NMR
(400 MHz, DMSO)
d
7.43 (d, J ¼ 8.0 Hz, 2H), 7.35 (d, J ¼ 8.1 Hz, 2H),
6.93 (d, J ¼ 8.3 Hz, 2H), 6.88 (d, J ¼ 8.1 Hz, 1H), 6.56 (s, 2H), 6.48 (q,
DMSO)
d 193.13, 153.04, 148.97, 147.46, 144.29, 137.09, 136.03,
J ¼ 12.2 Hz, 2H), 4.88 (s, 2H), 4.10 (s, 2H), 3.76 (s, 3H), 3.63 (d,
132.86, 130.04, 129.68, 129.13, 127.94, 122.69, 114.59, 112.42, 106.31,
69.74, 60.45, 56.03; HRMS m/z calcd for C26H27O 435.1802, found
435.1800 [M þ Hþ]; HPLC: tR 17.963 min, purity 96.065%.
(Z)-N-(2-aminoethyl)-1-(4-((2-methoxy-5-(3,4,5-
trimethoxystyryl)phenoxy)methyl)benzyl)piperidine-2-
carboxamide (TP6). The title compound was obtained as yellow oil
J ¼ 4.4 Hz, 9H); 13C NMR (101 MHz, DMSO)
d 153.09, 148.93, 147.70,
142.68, 137.10, 135.59, 132.98, 129.83, 129.56, 128.96, 127.85, 126.84,
122.42, 114.26, 112.28, 106.35, 70.16, 63.04, 60.45, 56.08, 55.97;
HRMS m/z calcd for C26H27O6 435.1813, found 435.1806 [M ꢀ Hþ];
HPLC: tR 15.086 min, purity 95.253%.
(Z)-1-(4-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)
methyl)benzyl)azetidine-3-carboxylic acid (TP11). The title com-
pound was obtained as white solid (3.1 mg, 15.2% yield); mp:
(2 mg, 15% yield); 1H NMR (400 MHz, CDCl3)
d
7.47 (d, J ¼ 7.9 Hz,
1H), 7.38 (d, J ¼ 8.1 Hz,1H), 7.10 (d, J ¼ 8.5 Hz, 0H), 6.91 (m,1H), 6.81
(d, J ¼ 8.2 Hz, 0H), 6.73 (s, 1H), 6.53 (s, 1H), 6.47 (q, J ¼ 12.1 Hz, 2H),
4.90 (s, 1H), 3.93 (s, 1H), 3.92 (s, 1H), 3.88 (d, J ¼ 3.8 Hz, 1H), 3.84 (s,
1H), 3.72 (s, 3H), 3.48 (s, 1H), 3.33 (d, J ¼ 9.1 Hz, 1H), 2.95 (s, 1H),
2.03 (s, 1H), 1.73 (d, J ¼ 7.1 Hz, 1H), 1.62 (m, 1H), 1.48 (d, J ¼ 9.3 Hz,
139.6e140.9 ꢁC; 1H NMR (400 MHz, DMSO)
d 7.24 (s, 4H), 6.92 (d,
J ¼ 8.3 Hz, 2H), 6.86 (d, J ¼ 10.1 Hz, 1H), 6.56 (s, 2H), 6.48 (d,
J ¼ 4.3 Hz, 2H), 5.33 (m, 1H), 4.81 (s, 2H), 3.74 (s, 3H), 3.63 (d,
J ¼ 2.6 Hz, 9H), 3.52 (d, J ¼ 3.8 Hz, 4H), 3.17 (d, J ¼ 1.2 Hz, 3H); 13
C
1H); 13C NMR (101 MHz, DMSO)
d
168.46, 152.93, 148.79, 147.34,
NMR (101 MHz, DMSO) d 173.33, 152.91, 148.80, 147.12, 141.16,
136.94, 134.60, 132.97, 132.12, 130.19, 130.03, 129.73, 129.52, 128.99,
127.97, 122.63, 114.27, 112.21, 106.26, 69.75, 65.64, 60.25, 56.06,
56.00, 40.15, 28.94, 28.79, 28.48; HRMS m/z calcd for C34H44O6N3
590.3225, found 590.3228 [M þ Hþ]; HPLC: tR 16.407 min, purity
95.660%.
136.80, 135.84, 133.04, 130.08, 129.70, 129.62, 129.07, 127.77, 122.96,
114.24, 112.34, 106.15, 69.66, 60.54, 55.96, 49.41, 37.17; HRMS m/z
calcd for C30H34O7N 520.2330, found 520.2324 [M þ Hþ]; HPLC: tR
15.103 min, purity 95.899%.
(3S,4S)-4-fluoro-1-(4-((2-methoxy-5-((Z)-3,4,5-
tert-butyl (Z)-(2-(1-(4-((2-methoxy-5-(3,4,5-trimethoxystyryl)
phenoxy)methyl)benzyl)piperidine-2-carboxamido)ethyl)carba-
mate (TP7). The title compound was obtained as yellow oil (20 mg,
trimethoxystyryl)phenoxy)methyl)benzyl)pyrrolidin-3-ol (TP12).
The title compound was obtained as yellow oil (6.5 mg, 23% yield);
1H NMR (400 MHz, DMSO)
d
7.27 (m, 4H), 6.92 (d, J ¼ 8.6 Hz, 2H),
25% yield); 1H NMR (400 MHz, DMSO)
d
7.81 (t, J ¼ 5.6 Hz, 1H), 7.33
6.87 (d, J ¼ 8.3 Hz, 1H), 6.56 (s, 2H), 6.48 (m, 2H), 5.31 (d, J ¼ 4.7 Hz,
1H), 4.81 (m, 3H), 4.16 (dd, J ¼ 24.2, 5.4 Hz,1H), 3.75 (s, 3H), 3.57 (m,
11H), 3.03 (dd, J ¼ 9.4, 6.7 Hz, 1H), 2.68 (m, 2H), 2.16 (d, J ¼ 15.1 Hz,
(d, J ¼ 7.8 Hz, 2H), 7.26 (d, J ¼ 8.0 Hz, 2H), 6.92 (d, J ¼ 8.1 Hz, 2H),
6.87 (dd, J ¼ 6.2, 2.0 Hz,1H), 6.77 (t, J ¼ 5.3 Hz,1H), 6.56 (s, 2H), 6.48
(m, 2H), 4.83 (s, 2H), 3.75 (s, 3H), 3.70 (d, J ¼ 13.3 Hz, 1H), 3.63 (d,
J ¼ 2.4 Hz, 9H), 3.16 (dd, J ¼ 12.3, 6.7 Hz, 2H), 3.08 (d, J ¼ 13.2 Hz,
1H), 3.00 (m, 2H), 2.70 (s, 1H), 2.67 (s, 1H), 2.00 (m, 1H), 1.87 (t,
J ¼ 10.8 Hz, 1H), 1.73 (dd, J ¼ 12.5, 2.4 Hz, 1H), 1.63 (dd, J ¼ 11.6,
4.2 Hz, 1H), 1.51 (m, 3H), 1.34 (s, 9H); 13C NMR (101 MHz, DMSO)
1H); 13C NMR (101 MHz, DMSO)
d 153.08, 148.92, 147.72, 137.10,
132.97, 129.81, 129.59, 128.99, 128.01, 122.44, 114.29, 112.27, 106.35,
75.57, 75.32, 70.16, 60.45, 59.25, 58.23, 56.07, 55.96; HRMS m/z
calcd for C30H35O6NF 524.2443, found 524.2455 [M þ Hþ]; HPLC: tR
17.533 min, purity 98.363%.
d
173.86, 158.60, 156.08, 153.07, 148.92, 147.72, 137.10, 132.96,
(R,Z)-1-(4-((2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)
methyl)benzyl)pyrrolidin-3-ol (TP13). The title compound was
obtained as yellow oil (5 mg, 19% yield); 1H NMR (400 MHz, DMSO)
130.06, 129.82, 129.59, 129.45, 129.00, 127.86, 122.41, 114.26, 112.27,
106.35, 78.06, 70.13, 60.45, 56.07, 55.96, 28.55, 26.94, 25.50, 22.49;
HRMS m/z calcd for
C
39H52O8N3 690.3749, found 690.3754
d
7.27 (q, J ¼ 8.1 Hz, 4H), 6.92 (d, J ¼ 8.4 Hz, 2H), 6.86 (dd, J ¼ 8.3,
[M þ Hþ]; HPLC: tR 19.400 min, purity 97.254%.
1.5 Hz, 1H), 6.56 (s, 2H), 6.48 (m, 2H), 4.82 (s, 2H), 4.68 (s, 1H), 4.17
(s, 1H), 3.75 (s, 3H), 3.57 (m, 11H), 2.68 (t, J ¼ 6.9 Hz, 1H), 2.58 (d,
J ¼ 0.8 Hz, 1H), 2.40 (s, 1H), 2.29 (s, 1H), 1.99 (m, 1H), 1.54 (d,
(4-((2-methoxy-5-((Z)-3,4,5-trimethoxystyryl)phenoxy)
methyl)benzyl)-
tained as white solid (4.2 mg, 19% yield); mp: 137.4e138.6 ꢁC; 1H
NMR (400 MHz, DMSO)
7.36 (d, J ¼ 6.9 Hz, 2H), 7.28 (d, J ¼ 8.0 Hz,
2H), 7.20 (s, 1H), 6.92 (d, J ¼ 8.3 Hz, 2H), 6.87 (dd, J ¼ 8.6, 1.1 Hz, 1H),
L-threonine (TP8). The title compound was ob-
J ¼ 7.9 Hz, 1H); 13C NMR (101 MHz, DMSO)
d 153.08, 148.92, 147.74,
d
137.11, 135.72, 132.96, 129.82, 129.59, 128.99, 128.92, 127.96, 122.41,
114.27, 112.27, 106.36, 70.18, 69.79, 62.96, 60.45, 59.79, 56.07, 55.96,
10