J. Chadwick et al. / Bioorg. Med. Chem. 18 (2010) 2586–2597
2595
(1H, ddd, J = 9.9, 6.2, 3.3 Hz, H-10), 2.78–2.61 (2H, H-9 and
CHHCO2H), 2.50 (1H, dd, J = 15.7, 3.3 Hz, CHHCO2H), 2.33 (1H, td,
J = 14.1, 4.0 Hz, H-4a), 2.08–2.00 (1H, m), 1.99–1.90 (1H, m),
89.8/89.6, 80.7/80.7, 79.2/78.8/78.5 (2C), 71.3/70.8, 51.9/51.8,
47.3, 45.6/45.0, 43.9/43.8, 42.0, 40.1/39.9, 37.5, 36.7, 36.5/36.5,
35.1/34.8, 34.3/34.3, 29.9, 29.4, 28.4, 28.3, 27.6/27.5, 26.0, 25.7/
25.7, 24.8/24.7, 20.0/20.0 and 12.7/12.6; IR (neat)/cmꢀ1 3730,
3626, 3334, 2933, 1698 (C@O), 1630 (C@O), 1514, 1452, 1365,
1250, 1169, 1049, 1007, 941, 875 and 733;HRMS (ESI)
C34H59N3NaO9 [M+Na]+ requires 676.4149, found 676.4176; Anal.
Calcd C34H59N3O9 requires: C, 62.46; H, 9.27; N, 6.43. Found: C,
61.99; H, 9.27; N, 6.25.
1.84–1.75 (1H, m), 1.73–1.64 (2H, m), 1.48–0.88 (14H, m) includ-
ing 1.41 (3H, s, 3Me), 0.97 (3H, d, J = 5.9 Hz, 6Me) and 0.88 (3H,
d, J = 7.5 Hz, 9Me); 13C NMR (100 MHz, CDCl3) d 176.1 (CO2H),
103.3, 89.4, 80.8, 70.9, 52.1, 43.9, 37.5, 37.4, 36.5, 35.9, 34.4,
29.8, 25.8, 24.7, 20.1 and 12.7; IR (neat)/cmꢀ1 3500 (O–H), 2941,
2877, 2360, 1714 (C@O), 1452, 1378, 1281, 1192, 1126, 1092,
1055, 1014, 943, 877 (O–O), 845 (O–O), 824 and 736; HRMS (CI)
C17H30NO6 [M+NH4]+ requires 344.20734, found 344.20673; Anal.
Calcd C17H26O6 requires: C, 62.56; H, 8.03. Found: C, 62.11; H, 8.53.
5.1.1.24. 10b-[2-(N1,N4-Di-tert-butoxycarbonylspermidine)-2-
oxoethyl]deoxoartemisinin 30. Compound 23 (443 mg, 1.28
mmol) and N-methylmorpholine (0.35 mL, 3.21 mmol) were added
to a solution of 27 (349 mg, 1.07 mmol) in anhydrous CH2Cl2
(10 mL) and the solution was stirred at 0 °C for 10 min. To this
solution were added EDC hydrochloride (246 mg, 1.28 mmol) and
HOBt (173 mg, 1.28 mmol) and the mixture allowed to warm to
room temperature and stirred overnight. The mixture was then di-
luted with CH2Cl2 (40 mL) and washed with 2.0 M aq HCl
(4 ꢂ 20 mL), saturated aq NaHCO3 (4 ꢂ 20 mL) and brine (20 mL).
The organic phase was dried over Na2SO4, filtered and concen-
trated under reduced pressure to give a colourless oil. Purification
by flash column chromatography (silica gel, 65:35 EtOAc/n-Hex)
gave 30 (433 mg, 62%) as a white solid. Compound 30: 1H NMR
(400 MHz, CDCl3) d 7.10 (1H, br s, NH), 5.38 (1H, s), 5.04 (1H, br
s, NH), 4.88–4.67 (1H, m, H-10), 3.48–3.32 (1H, m), 3.32–3.02
(8H, m), 2.65–2.46 (2H, m, H-9 and C(O)CHH), 2.40–2.26 (2H, m,
5.1.1.22. 10b-[2-(N4,N8-Di-tert-butoxycarbonylspermidine)-2-
xoethyl]deoxoartemisinin 28. Compound 13 (369 mg, 1.07
mmol) and N-methylmorpholine (0.29 mL, 2.67 mmol) were added
to a solution of 27 (291 mg, 0.89 mmol) in anhydrous CH2Cl2
(10 mL) and the solution was stirred at 0 °C for 10 min. To this
solution were added EDC hydrochloride (205 mg, 1.07 mmol) and
HOBt (144 mg, 1.07 mmol) and the mixture allowed to warm to
room temperature and stirred overnight. The mixture was then di-
luted with CH2Cl2 (40 mL) and washed with 2.0 M aq HCl
(4 ꢂ 20 mL), saturated aq NaHCO3 (4 ꢂ 20 mL) and brine (20 mL).
The organic phase was dried over Na2SO4, filtered and concen-
trated under reduced pressure to give a colourless oil. Purification
by flash column chromatography (silica gel, 65:35 EtOAc/n-Hex)
gave 28 (386 mg, 66%) as a white solid. Compound 28: mp 55–
58 °C; 1H NMR (400 MHz, CDCl3) d 7.08 (1H, br s, NH), 5.39 (1H,
s, H-12), 4.76 (1H, m, H-10), 4.50 (1H, br s, NH), 3.42–3.05 (8H,
H-4a and C(O)CHH), 2.12–2.02 (1H, m), 2.02–1.93 (1H, m), 1.85–
1.43 (10H, m), 1.46 (9H, s, t-Bu), 1.44 (9H, s, t-Bu), 1.39 (3H, s,
3Me), 1.36–1.16 (3H, m), 0.98 (3H, d, J = 5.0 Hz, 6Me) and 0.88
(3H, d, J = 7.5 Hz, 9Me); NMR (100 MHz, CDCl3). Two rotamers d
171.3/170.1, 155.8, 155.2, 104.2/102.6, 91.5/89.8, 80.5, 79.2, 78.5,
69.7/69.5, 51.5/51.4, 46.3/46.0, 44.0/43.4, 43.2, 38.7/38.6, 37.5/
37.1, 37.3, 36.2/35.8, 34.0/33.8, 30.1, 28.6/28.0, 28.2 (2C), 26.6,
25.8/25.6, 25.8/25.2, 24.5, 24.5, 20.0/19.8 and 13.8; IR (neat)/
cmꢀ1 3730, 3626, 3342, 2929, 1678 (C@O), 1529, 1419, 1367,
1250, 1167, 1092, 1049, 1009, 876 and 733; HRMS (ESI)
C34H59N3NaO9 [M+Na]+ requires 676.4149, found 676.4178; Anal.
Calcd C34H59N3O9 requires: C, 62.46; H, 9.27; N, 6.43. Found: C,
61.85; H, 9.29; N, 6.29.
m), 2.70–2.44 (2H, m, H-9 and C(O)CHH), 2.39–2.25 (2H, m, H-4
a
and C(O)CHH), 2.16–1.91 (2H, m), 1.86–1.44 (11H, m), 1.45 (9H,
s, t-Bu), 1.44 (9H, s, t-Bu), 1.39 (3H, s, 3Me), 1.35–1.18 (3H, m),
0.97 (3H, d, J = 5.4 Hz, 6Me) and 0.87 (3H, d, J = 7.5 Hz, 9Me); 13C
NMR (100 MHz, CDCl3) d 171.5, 155.9, 155.5, 102.8, 89.8, 80.7,
79.3, 78.9, 70.5, 51.8, 46.7, 45.0, 44.1, 43.6, 43.3, 37.4, 37.0, 36.4,
34.1, 33.9, 30.2, 28.9, 28.3, 27.9, 27.3, 25.7, 24.7, 21.0, 19.9 and
13.9; IR (neat)/cmꢀ1 3726, 3336, 2933, 1680 (C@O), 1529, 1419,
1367, 1250, 1169, 1093, 1047, 1007, 875, 771 and 732; HRMS
(ES) C34H59N3NaO9 [M+Na]+ requires 676.4149, found 676.4158;
Anal. Calcd C34H59N3O9 requires: C, 62.46; H, 9.27; N, 6.43. Found:
C, 62.84; H, 9.14; N, 6.40.
5.1.1.25. 10b-[2-N1-Spermidine)-2-oxoethyl]deoxoartemisinin
dihydrochloride 31. To a stirring solution of 28 (150 mg, 0.23
mmol) in anhydrous 1,4-dioxane (2 mL) was added excess 4.0 M
HCl in 1,4-dioxane (2 mL). After stirring for 3 h, the solvent was re-
moved under reduced pressure to give a sticky yellow semisolid.
This reside was triturated with diethyl ether to give a bright yellow
solid. Filtration of the solid under a nitrogen atmosphere and
washing with diethyl ether gave 31 (108 mg, 89%) as a bright yel-
low hygroscopic solid. Compound 31: 1H NMR (400 MHz, CDCl3) d
5.53 (1H, s, H-12), 4.50 (1H, m, H-10), 3.20–2.95 (8H, m), 2.85–2.70
5.1.1.23. 10b-[2-(N1,N8-Di-tert-butoxycarbonylspermidine)-2-
oxoethyl]deoxoartemisinin 29. Compound 16 (306 mg, 0.87
mmol) and N-methylmorpholine (0.24 mL, 2.22 mmol) were added
to a solution of 27 (241 mg, 0.74 mmol) in anhydrous CH2Cl2
(10 mL) and the solution was stirred at 0 °C for 10 min. To this
solution were added EDC hydrochloride (170 mg, 0.87 mmol) and
HOBt (120 mg, 0.87 mmol) and the mixture allowed to warm to
room temperature and stirred overnight. The mixture was then di-
luted with CH2Cl2 (40 mL) and washed with 2.0 M aq HCl
(4 ꢂ 20 mL), saturated aq NaHCO3 (4 ꢂ 20 mL) and brine (20 mL).
The organic phase was dried over Na2SO4, filtered and concen-
trated under reduced pressure to give a colourless oil. Purification
by flash column chromatography (silica gel, 65:35 EtOAc/n-Hex)
gave 29 (344 mg, 71%) as a white solid. Compound 29: mp 56–
58 °C; 1H NMR (400 MHz, CDCl3). Two rotamers d 5.68 (1H, br t,
J = 5.8 Hz, NH), 5.33 (1/3H, s, H-12), 5.31 (2/3H, s, H-12), 4.98–
4.84 (1H, m, H-10), 4.73 (1H, br s, NH), 3.67–3.49 (1H, m), 3.48–
3.25 (3H, m), 3.25–2.97 (5H, m), 2.79–2.63 (2H, m, H-9 and
(2H, m, H-9 and C(O)CHH), 2.41–2.27 (2H, m, H-4a and C(O)CHH),
2.16–1.38 (14H, m), 1.33 (3H, s, 3Me), 1.31–1.19 (2H, m), 0.98 (3H,
d, J = 6.3 Hz, 6Me) and 0.91 (3H, d, J = 7.3 Hz, 9Me); 13C NMR
(100 MHz, CDCl3) d 176.0, 105.0, 90.0, 82.3, 75.7, 54.1, 48.3, 46.1,
45.8, 40.1, 38.2, 37.6, 37.4, 36.3, 35.8, 30.9, 27.6, 26.3, 25.8, 25.6,
24.4, 23.2, 20.7 and 13.8; IR (neat)/cmꢀ1 3830, 3730, 3624, 2952,
1709, 1645 (C@O), 1547, 1458, 1379, 1265, 1205, 1092, 1045,
876 and 731; HRMS (ESI) C24H44N3O5 [M– (2HCl)+H]+ requires
454.3281, found 454.3301.
C(O)CHH), 2.43–2.25 (2H, m, H-4
a and C(O)CHH), 2.08–1.89 (2H,
m), 1.87–1.75 (2H, m), 1.75–1.48 (8H, m), 1.44 (2/3 ꢂ 18H, s,
2 ꢂ t-Bu), 1.42 (1/3 ꢂ 18H, s, 2ꢂt-Bu), 1.39 (1/3 ꢂ 3H, 3Me), 1.37
(2/3 ꢂ 3H, 3Me), 1.35–1.20 (3H, m), 0.97 (3H, d, J = 5.8 Hz, 6Me)
and 0.88 (3H, d, J = 7.5 Hz, 9Me); 13C NMR (100 MHz, CDCl3). Two
5.1.1.26. 10b-[2-N4-Spermidine)-2-oxoethyl]deoxoartemisinin
dihydrochloride 32. To a stirring solution of 28 (287 mg, 0.44
mmol) in anhydrous 1,4-dioxane (2 mL) was added excess 4.0 M
HCl in 1,4-dioxane (2 mL). After stirring for 3 h the solvent was re-
moved under reduced pressure to give a sticky yellow semisolid.
rotamers
d 171.7/170.9, 156.2/156.0/155.9 (2C), 102.9/102.7,