Arch. Pharm. Chem. Life Sci. 2010, 8, 449–457
Novel Betulinic Acid and Betulin Derivatives
455
0.95 (C27H3), 1.09 and 1.66 (C15H2), 1.15 and 1.43 (C12H2), 1.18
and 1.48 (C11H2), 1.29 (C400H2–C800H2), 1.38 and 1.61 (C6H2), 1.39
(C9H), 1.41 (C5H), 1.42 and 1.60 (C21H2), 1.43 (C300H2/C800H2), 1.49
(C400H2), 3.00 (C900H2), 1.59 and 1.67 (C2H2), 1.61 (C13H), 1.62
(C200H2), 1.65 (C7H2), 1.77 (C500H2), 1.80 and 2.04 (C16H2), 1.85
and 2.20 (C22H2), 2.03 (C30H3), 2.17 (C20H2), 2.19 (C19H), 2.23
(C18H), 3.00 (C1000H2), 4.07 (C100H2), 4.45 (C3H), 4.59 and 4.72
(C29H3); 13C NMR (125 MHz, CDCl3) d (in ppm): 14.6 (C27), 16.0
(C26), 16.1 (C25), 16.4 (C24), 18.1 (C6), 19.3 (C30), 20.9 (C11), 21.2 (C20),
23.6 (C2), 25.5 (C12), 25.7 (C300/C800), 27.6 (C15), 27.9 (C23), 28.7 (C200),
29.4 (C400), 29.5 (C500–C700), 29.6 (C16), 30.6 (C21), 32.2 (C900), 34.2 (C22),
34.3 (C7), 37.1 (C10), 37.8 (C13), 38.3 (C1), 38.4 (C4), 40.7 (C8), 42.4
(C14), 44.8 (C17), 47.0 (C18), 49.3 (C19), 50.4 (C9), 63.1 (C1000), 63.9
(C100), 56.5 (C5), 80.9 (C3)þ, 109.5 (C29), 150.6 (C20), 171.0/176.2 (C28/
C10). LC/MS/MS [M þ H] : 672.04.
3-O-Laurylbetulinic acid 11
A mixture of betulinic acid (228 mg, 0.5 mmol) and dodecanoic
anhydride (200 mg, 0.5 mmol) in dichloromethane was stirred
with full microwave power (300 W) at 908C under a maximum
pressure of 10 bar for 45 min to obtain a brownish-white
crystalline powder. It was purified by column chromatograph
(dichloromethane/methanol, 8:2) on silica gel. Yield: 171 mg
(75%) as a white solid; 1H-NMR (500 MHz, CDCl3) d (in ppm):
0.81 (C110H3), 0.85 (C24H3), 0.87 and 1.66 (C1H2), 0.91 (C23H3),
1.04 and 1.67 (C15H2), 1.17 and 1.47 (C11H2), 1.18 and 1.48
(C12H2), 1.24 (C25H3/C26H3/C27H3), 1.33 (C50H2/C60H2/C70H2),
1.36 (C40H2/C80H2/C90H2), 1.37 and 1.59 (C6H2), 1.38
(C100H2),1.39 (C9H), 1.40 (C5H), 1.41 and 1.61 (C21H2), 1.57
(C30H2), 1.58 (C7H2), 1.58 and 1.83 (C22H2), 1.59 and 1.65
(C2H2), 1.62 and 2.01 (C16H2), 1.63 (C13H), 1.93 (C18H), 1.94
(C30H3), 2.17 (C19H), 2.34 (C20H2), 4.43 (C3H), 4.58 and 4.70
13
(C29H3); C-NMR (125 MHz, CDCl3) d (in ppm): 14.2 (C110), 14.8
3-O-Chloroacetylbetulinic acid 9
(C27), 16.2 (C24), 16.3 (C25), 16.7 (C26), 18.4 (C6), 19.5 (C30), 21.1
(C11), 22.8 (C100), 23.9 (C12), 24.9 (C80), 25.6 (C2), 28.1 (C23), 29.2 (C40),
29.4 (C50/C80), 29.6 (C60/C70), 29.8 (C21), 30.7 (C15), 25.3 (C30), 32.0
(C90), 32.3 (C16), 34.3 (C20), 35.0 (C7), 37.2 (C22), 37.2 (C10), 38.0 (C4),
38.5 (C13), 38.6 (C1), 40.9 (C8), 42.6 (C14), 47.0 (C18), 49.4 (C19), 50.6
(C9), 55.7 (C5), 56.5 (C17), 80.7 (C3), 109.7 (C29), 150.3 (C20), 173.6
(C10), 182.7 (C28). LC/MS/MS [M þ H]þ: 626.06.
A mixture of betulinic acid (228 mg, 0.5 mmol) and chloroacetic
anhydride (170 mg, 1 mmol) in hexane (3 mL) was stirred with
full microwave power (300 W) at 948C under a maximum pres-
sure of 10 bar for 20 min. After separation by column chroma-
tography with silica gel (eluent: dichloromethane/methanol,
10:0.1), it yielded a white powder. White solid; yield: 162 mg
(71%); 1H-NMR (500 MHz, CDCl3) d (in ppm): 0.77 and 1.70 (C1H2),
0.83 (C24H3), 0.84 (C23H3), 0.85 (C25H3), 0.92 (C26H3), 0.96
(C27H3), 1.04 and 1.69 (C15H2), 1.15 and 1.46 (C12H2), 1.18 and
1.48 (C11H2), 1.37 and 1.60 (C6H2), 1.39 (C9H), 1.41 (C5H), 1.42 and
1.60 (C21H2), 1.59 and 1.94 (C22H2), 1.60 and 1.67 (C2H2), 1.62
(C13H), 1.63 (C7H2), 1.72 and 2.02 (C16H2), 1.92 (C18H), 1.97
(C30H3), 2.17 (C19H), 4.02 (C2’H2), 4.53 (C3H), 4.59 and 4.72
(C29H3); 13C-NMR (125 MHz, CDCl3) d (in ppm): 14.7 (C27), 16.1
(C25), 16.2 (C26), 16.4 (C24), 18.2 (C6), 19.4 (C30), 20.9 (C11), 23.6
(C12), 25.5 (C2), 28.0 (C23), 29.7 (C21), 30.6 (C15), 32.2 (C16), 34.3 (C7),
37.1 (C10), 37.2 (C22), 38.1 (C4), 38.4 (C1), 38.5 (C13), 40.8 (C8), 41.2
(C20), 42.5 (C14), 47.0 (C18), 49.3 (C19), 50.4 (C9), 55.4 (C5), 56.4 (C17),
83.3 (C3), 109.7 (C29), 150.2 (C20), 167.0 (C10), 182.1 (C28). LC/MS/MS
[M þ H]þ: 534.1.
28-O-Chloracetylbetulin 15
A mixture of betulin (442 mg, 1 mmol) and chloroacetic anhy-
dride (170 mg, 1 mmol) in dichloromethane (3 mL) was stirred
with full microwave power (250 W) at 908C under a maximum
pressure of 10 bar for 20 min. After separation by column
chromatography with silica gel (eluent: dichloromethane/meth-
anol, 10:0.1), it yielded a white powder. White solid; yield:
385 mg (87%); 1H-NMR (500 MHz, CDCl3) d (in ppm): 0.74
(C24H3), 0.80 (C25H3), 0.87 and 1.64 (C1H2), 0.94 (C27H3), 0.95
(C23H3), 1.00 (C26H3), 1.02 and 1.82 (C22H2), 1.05 and 1.63
(C12H2), 1.06 and 1.72 (C15H2), 1.19 and 1.50 (C11H2), 1.21 and
1.94 (C16H2), 1.27 (C9H), 1.39 (C7H2), 1.51 and 1.97 (C21H2), 1.59
(C2H2/C18H), 3.15 (C3H), 0.64 (C5H), 1.37 and 1.55 (C6H2), 1.63
(C13H), 1.66 (C30H3), 2.42 (C19H), 3.93 and 3.96 (C28H2), 4.34
(C200H2), 4.57 and 4.67 (C29H3); 13C-NMR (125 MHz, CDCl3) d (in
ppm): 14.9 (C27), 15.4 (C24), 16.1 (C25/C26), 18.4 (C6), 19.2 (C30), 20.9
(C11), 25.3 (C12), 27.1 (C15), 27.5 (C2), 28.1 (C23), 29.6 (C21), 29.8
(C16), 34.3 (C22), 34.5 (C7), 37.2 (C10), 37.7 (C13), 38.8 (C1), 38.9 (C4),
40.9 (C8/C200), 42.7 (C14), 46.6 (C17), 47.1 (C18), 48.9 (C19), 50.4 (C9),
55.4 (C5), 64.8 (C28), 78.9 (C3), 109.8 (C29), 149.7 (C20), 167.4 (C100).
LC/MS/MS [M ꢁ H]ꢁ: 518.2.
3-O-Hexanoylbetulinic acid 10
A mixture of betulinic acid (1350 mg, 3 mmol) and hexanoic
anhydride (6 mL, 25 mmol) in dichloromethane (9 mL) was
stirred with full microwave power (300 W) at 908C under a
maximum pressure of 10 bar for 30 min. The reaction mixture
was separated with column chromatography (dichlorome-
thane/methanol, 10:1) to obtain a white powder. White solid;
yield: 850 mg (63%); 1H-NMR (500 MHz, CDCl3) d (in ppm): 0.81
(C60H3), 0.83 (C24H3), 0.87 and 1.66 (C1H2), 0.91 (C23H3), 0.95
(C25H3/C26H3/C27H3), 1.05 and 1.67 (C15H2), 1.15 and 1.45
(C11H2), 1.18 and 1.48 (C12H2), 1.30 (C40H2), 1.34 (C50H2), 1.38
and 1.59 (C6H2), 1.39 (C9H), 1.41 (C5H), 1.42 and 1.62 (C21H2),
1.57 (C30H2), 1.58 (C7H2), 1.59 and 1.83 (C22H2), 1.60 and 1.64
(C2H2), 1.62 and 2.01 (C16H2), 1.64 (C13H), 1.70 (C30H2), 1.94
(C18H), 1.96 (C30H3), 2.17 (C19H), 2.26 (C20H2), 2.34 (C20H2), 4.43
(C3H), 4.59 and 4.71 (C29H3); 13C-NMR (125 MHz, CDCl3) d (in
ppm): 14.0 (C60), 14.8 (C27), 16.2 (C24), 16.3 (C25), 16.6 (C26), 18.3
(C6), 19.5 (C30), 21.0 (C11), 22.4 (C50), 23.9 (C12), 24.9 (C40), 25.6 (C2),
28.1 (C23), 29.8 (C21), 30.7 (C15), 31.4 (C30), 32.3 (C16), 34.4 (C20),
34.9 (C7), 37.1 (C10/C22), 37.2 (C4), 37.9 (C1), 38.5 (C13), 40.8 (C8),
42.5 (C14), 47.0 (C18), 49.4 (C19), 50.5 (C9), 53.4 (C5), 55.5 (C17), 80.6
(C3), 109.7 (C29), 150.2 (C20), 173.5 (C10), 180.5 (C28). LC/MS/MS
[M þ H]þ: 555.7.
28-O-Laurylbetulin 16
A mixture of betulin (442 mg, 1 mmol) and lauric anhydride
(383 mg, 2 mmol) in dichloromethane (3 mL) was stirred with
full microwave power (300 W) at 908C under a maximum pres-
sure of 10 bar for 20 min. After separation by column chroma-
tography with silica gel (eluent: dichloromethane/methanol,
10:0.05), it yielded a white powder. White solid; yield: 287 mg
(65%); 1H-NMR (500 MHz, CDCl3) d (in ppm): 0.65 (C5H), 0.73
(C24H3), 0.83 (C25H3), 0.89 and 1.64 (C1H2), 0.93 (C27H3), 0.94
(C23H3), 1.00 (C26H3), 1.02 and 1.81 (C22H2), 1.05 and 1.63
(C12H2), 1.06 and 1.71 (C15H2), 1.19 and 1.48 (C11H2), 1.22 and
1.93 (C16H2), 1.25 (C500H2/C600H2/C700H2), 1.26 (C9H), 1.36 (C400H2/
C800H2/C900H2), 1.38 and 1.53 (C6H2), 1.39 (C7H2), 1.49 and 1.96
(C21H2), 1.55 (C300H2), 1.57 (C2H2), 1.58 (C18H), 1.63 (C13H), 1.67
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