Y. Hu et al.
Bioorganic Chemistry 111 (2021) 104903
eq) were dissolved in dry CH2Cl2 (20 ml). Then added EDCl (1.2 mmol,
1.2 eq) and cooled to 0 ◦C. After addition of ethanolamine (1.2 mmol,
1.2 eq) the reaction mixture was slowly warmed to room temperature
and stirred overnight. The organic layer was washed by saturated so-
dium chloride three times. The combined organic layers dried over
Na2SO4, filtered and concentrated under reduced pressure. The crude
products were purified by column chromatography to obtain the target
compounds.
22.1, 20.2, 12.6. HRMS (ESI) calculated for C28H39NO8Na [M + Na]+
540.2573, found 540.2564.
4.2.3.5. Compound 16e. The product was obtained as yellow solid (103
mg, 62%). ESI-MS: m/z 498 [M + Na]+. 1H NMR (300 MHz, CDCl3) δ
7.59 (d, J = 15.8 Hz, 1H), 7.52–7.48 (m, 2H), 7.04 (d, J = 8.6 Hz, 2H),
6.88 (s, 1H), 6.44 (d, J = 15.7 Hz, 1H), 5.41 (s, 1H), 4.49 (d, J = 9.2 Hz,
1H), 3.93–3.86 (m, 2H), 3.70 (d, J = 11.6 Hz, 1H), 3.57–3.52 (m, 1H),
2.45–0.91(m, 21H) including three typical-CH3 of DHA such as 1.42 (s,
3H), 0.98 (d, J = 5.6 Hz, 3H), 0.93 (d, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 165.0, 161.6, 139.3, 129.6, 129.5, 121.2, 116.0, 115.9,
115.7, 104.3, 102.8, 91.3, 80.2, 68.3, 51.5, 45.3, 40.0, 37.4, 36.2, 34.1,
32.5, 26.0, 24.7, 22.1, 20.2, 12.6. HRMS (ESI) calculated for
4.2.3. General procedure for synthesis of hybrids 16a-h
Artemisinin and compound 15a-h were dissolved in dry CH2Cl2 in
three-necked flask. While cooling to 0 ◦C, the boron trifluoride etherate
was added under the protection of N2. The reaction was stirred for two
hours at the same condition. The reaction mixture was washed with
saturated NaHCO3 solution and brine. The combined organic layers
dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude products were purified by column chromatography to obtain
the target compounds.
C
26H34FNO6Na [M + Na]+ 498.2268, found 498.2258.
4.2.3.6. Compound 16f. The product was obtained as yellow solid (72
mg, 41%). ESI-MS: m/z 525 [M + Na]+. 1H NMR (300 MHz, CDCl3) δ
7.59 (dd, J = 15.6, 2.5 Hz, 1H), 7.49 (dd, J = 7.3, 4.3 Hz, 2H), 7.05 (t, J
= 8.5 Hz, 2H), 6.87 (s, 1H), 6.40 (dd, J = 24.9, 15.6 Hz, 1H), 5.41 (d, J =
4.4 Hz, 1H), 4.45 (t, J = 16.4 Hz, 1H), 3.86 (m, 2H), 3.79–3.50 (m, 2H),
2.67–0.91(m, 21H) including three typical-CH3 of DHA such as 1.43 (d,
J = 10.7 Hz, 3H), 0.97–0.92 (m, 3H), 0.92 (d, J = 6.3 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 165.0, 161.6, 139.3, 129.6, 129.5, 121.2, 116.0,
115.9, 115.7, 104.3, 102.8, 91.3, 80.2, 68.3, 51.5, 45.3, 40.0, 37.4, 36.2,
34.1, 32.5, 26.0, 24.7, 22.1, 20.2, 12.6. HRMS (ESI) calculated for
4.2.3.1. Compound 16a. The product was obtained as white solid (86
mg, 54%). ESI-MS: m/z 458 [M + H]+. 1H NMR (300 MHz, CDCl3) δ 7.63
(d, J = 15.0 Hz, 1H), 7.51 (s, 2H), 7.35 (s, 3H), 6.89 (s, 1H), 6.52 (d, J =
15.5 Hz, 1H), 5.41 (s, 1H), 4.49 (d, J = 9.1 Hz, 1H), 3.90 (s, 2H), 3.68 (s,
1H), 3.55 (s, 1H), 2.67–0.91 (m, 21H) including three typical-CH3 of
DHA such as 1.43 (s, 3H), 0.97 (d, J = 5.2 Hz, 3H), 0.92 (d, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 158.0, 149.1, 140.5, 129.5, 128.6 (C ×
2), 127.8 (C × 2), 121.1, 104.4, 100.9, 91.3, 84.3, 68.9, 51.4, 45.1, 40.1,
37.4, 36.1, 34.1, 32.4, 26.1, 24.6, 22.2, 20.2, 12.4. HRMS (ESI) calcu-
lated for C26H35NO6Na [M + Na]+ 480.2362, found 480.2349.
C
26H34N2O8Na [M + Na]+ 525.2213, found 525.2227.
4.2.3.7. Compound 16g. The product was obtained as yellow solid (103
mg, 56%). ESI-MS: m/z 548 [M + Na]+. 1H NMR (300 MHz, CDCl3) δ
7.59 (s, 5H), 7.09 (s, 1H), 6.58 (d, J = 15.6 Hz, 1H), 5.39 (s, 1H), 4.45 (d,
J = 12.6 Hz, 1H), 3.94 (m, 2H), 3.70–3.50 (m, 2H), 2.67–0.91(m, 21H)
including three typical-CH3 of DHA such as 1.43 (d, J = 10.7 Hz, 3H),
0.97–0.92 (m, 3H), 0.92 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
165.4, 139.3, 138.7, 127.9, 125.7, 125.6, 123.9, 104.5, 104.3, 102.9,
100.9, 91.3, 88.0, 80.3, 68.8, 51.5, 45.3, 40.1, 37.4, 36.2, 34.1, 32.5,
26.0, 25.0, 22.1, 20.2, 12.6. HRMS (ESI) calculated for C27H34F3NO6Na
[M + Na]+ 548.2236, found 548.2242.
4.2.3.2. Compound 16b. The product was obtained as yellow solid (102
mg, 60%). ESI-MS: m/z 510 [M + Na]+. 1H NMR (300 MHz, CDCl3) δ
7.60 (d, J = 15.8 Hz, 1H), 7.48 (m, 2H), 6.90 (d, J = 8.6 Hz, 2H), 6.79 (s,
1H), 6.39 (d, J = 15.8 Hz, 1H), 5.41 (s, 1H), 4.49 (d, J = 9.4 Hz, 1H),
3.91 (s, 2H), 3.85 (s, 3H), 3.70 (s, 1H), 3.57 (s, 1H), 2.68–0.92(m, 21H)
including three typical-CH3 of DHA such as 1.44 (s, 3H), 0.98 (d, J = 5.7
Hz, 3H), 0.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.4, 160.7, 140.1,
129.3 (C × 2), 127.7, 118.9, 114.1 (C × 2), 102.6, 100.8, 91.2, 80.4,
68.9, 55.3, 51.5, 45.3, 39.9, 37.4, 36.3, 34.1, 32.5, 26.0, 24.7, 22.1,
22.1, 20.2, 12.6. HRMS (ESI) calculated for C27H37NO7Na [M + Na]+
510.2468, found 510.2459.
4.2.3.8. Compound 16h. The product was obtained as yellow solid (89
mg, 52%). ESI-MS: m/z 514 [M + Na]+. 1H NMR (300 MHz, CDCl3) δ
7.57 (d, J = 15.7 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz,
2H), 6.97 (s, 1H), 6.50 (d, J = 15.7 Hz, 1H), 5.40 (s, 1H), 4.48 (d, J = 9.3
Hz, 1H), 3.96–3.83 (m, 2H), 3.69 (d, J = 13.9 Hz, 1H), 3.52 (d, J = 4.1
Hz, 1H), 2.44–0.85 (m, 21H) including three typical-CH3 of DHA such as
1.27 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H). 13C NMR (75 cMHz, CDCl3) δ
165.7, 139.1, 133.6, 129.0 (C × 4), 121.9, 104.5, 102.8, 100.9, 91.3,
80.4, 68.8, 51.5, 45.3, 40.0, 37.4, 36.2, 34.1, 32.5, 26.0, 24.7, 22.1,
20.2, 12.6. HRMS (ESI) calculated for C26H34ClNO6Na [M + Na]+
514.1972, found 514.1963.
4.2.3.3. Compound 16c. The product was obtained as yellow solid (86
mg, 52%). ESI-MS: m/z 494 [M + Na]+. 1H NMR (300 MHz, DMSO‑d6) δ
8.05 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 16.1 Hz, 1H), 7.20 (d,
J = 7.8 Hz, 2H), 6.59 (d, J = 15.8 Hz, 1H), 5.41 (s, 1H), 4.49 (d, J = 9.2
Hz, 1H), 3.76 (dd, J = 10.0, 5.3 Hz, 1H), 3.56–3.48 (m, 1H), 3.35 (d, J =
5.6 Hz, 2H), 2.30 (s, 3H), 2.30–0.78 (m, 21H) including three typical-
CH3 of DHA such as 1.27 (s, 3H), 0.87 (d, J = 6.1 Hz, 3H), 0.79 (d, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 166.2, 140.4, 139.6, 132.2 (C
× 2), 129.4, 127.8, 120.1 (C × 2), 104.2, 100.8, 91.2, 80.3, 69.0, 51.5,
45.3, 40.0, 37.4, 36.3, 34.1, 32.5, 26.0, 24.7, 22.1, 22.1, 20.2, 12.6.
HRMS (ESI) calculated for C27H37NO6Na [M + Na]+ 494.2519, found
494.2508.
4.2.4. General procedure for synthesis of hybrids 18a-e
The corresponding benzaldehyde (1 mmol, 1 eq) and Cyanoacetic
acid (1.11 mmol, 1.11 eq) were dissolved in toluene (10 ml). Then
ammonium acetate (0.17 mmol, 0.17 eq) was added as catalyst. The
reaction mixture was stirred at 100 ◦C for 7 h. Filtered, the filter cake
was washed three times with the filtrate and dried under vacuum to
obtain the target compounds.
4.2.3.4. Compound 16d. The product was obtained as yellow solid (89
mg, 49%). ESI-MS: m/z 540 [M + Na]+. 1H NMR (500 MHz, CDCl3) δ
7.59 (d, J = 15.9 Hz, 1H), 7.13 – 7.09 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H),
6.79 (s, 1H), 6.43 (d, J = 15.5 Hz, 1H), 5.44 (s, 1H), 4.52 (d, J = 9.3 Hz,
1H), 3.94 (d, J = 3.4 Hz, 6H), 3.90 (dd, J = 11.6, 8.8 Hz, 2H), 3.74 (dd, J
= 15.3, 8.5 Hz, 1H), 3.56 (s, 1H), 2.51–0.95 (m, 21H) including three
typical-CH3 of DHA such as 1.45 (s, 3H), 1.00 (d, J = 5.9 Hz, 3H), 0.95
(d, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 166.3, 149.3 (C × 2),
140.1, 130.2 (C × 2), 128.2, 124.7, 121.9, 110.7, 100.8, 91.3, 80.4,
68.9, 55.9, 55.8, 51.5, 45.3, 40.0, 37.4, 36.3, 34.2, 32.6, 26.0, 24.7,
4.2.5. General procedure for synthesis of hybrids 18a-e
To a solution of 50% glyoxylic acid (0.95 mmol, 0.95 eq), the cor-
responding benzeneacetonitrile (1 mmol, 1 eq) and K2CO3 (1.5 mmol,
◦
1.5 eq) in methanol (10 ml) was stirred at 60 C for 5–8 h until TLC
showed the reaction was completed. Then filtered, the filter cake was
washed three times with CH2Cl2。 Afterwards the filter cake was dis-
solved in water and using hydrochloric acid to adjust pH to 4. The
10