Synthesis and Biological Evaluation of Novel Pentacyclic
Medicinal Chemistry, 2013, Vol. 9, No. 1 123
Preparation of (S)2-{4-[2-(tert-Butoxycarbonylamino)-3-
methoxy-3-oxopropyl]phenoxy}ethyl 3ꢀ-hydroxyurs-12-
en-28-oate (16)
170.1, 158.1, 143.6, 130.3, 128.2, 122.5, 115.0, 79.1, 66.0,
62.5, 55.2, 53.7, 47.6, 46.8, 45.9, 41.7, 41.3, 39.4, 38.7, 38.5,
37.9, 37.0, 33.9, 33.1, 32.7, 32.4, 30.7, 28.1, 27.6, 27.2, 25.9,
23.6, 23.4, 23.0, 18.3, 17.0, 15.6, 15.3; MS (ESI, m/z):
704.5 (M-H-, base peak); HRMS for C42H59N1O6S1+Na
calcd 728.39608, found 728.39553.
Compound 16 could be prepared following the procedure
described for 5. white solid, yield 79%, m.p. 88-90 °C. IR
1
(KBr, ꢁ): 3541, 2924, 1720, 1512; H NMR (CDCl3, 300
MHz, ꢅppm): 0.72 (s, 3H), 0.77 (s, 3H), 0.84 (d, 3H, J = 6.5
Hz), 0.87 (s, 3H), 0.94 (s, 3H), 0.98 (s, 3H), 1.06 (s, 3H),
1.42 (s, 9H), 2.24 (d, 1H, J = 11.32 Hz), 2.97-3.07 (m, 2H),
3.18-3.23 (m, 1H), 3.71 (s, 3H), 4.10 (t, 2H, J = 4.7 Hz),
4.33 (t, 2H, J = 4.2 Hz), 4.56-4.57 (m, 1H), 4.95-4.98 (m,
1H), 5.22 (t, 1H, J = 3.3 Hz), 6.80 (dd, 2H, J = 8.62, 65.2
Hz), 7.03 (dd, 2H, J = 8.54, 65.1 Hz); 13C NMR (CDCl3, 75
MHz, ꢅppm): 177.4, 172.3, 157.8, 138.0, 130.3,
128.4, 125.7, 114.7, 79.0, 65.9, 62.5, 55.3, 52.9,
52.1, 48.2, 47.6, 42.1, 39.6, 39.1, 38.8, 38.7, 38.7,
37.0, 36.6, 33.0, 30.7, 28.3, 28.1, 28.0, 27.3, 24.2,
23.5, 23.3, 21.1, 18.3, 17.1, 17.0, 15.6, 15.4; MS
Preparation of 2-{4-[(2,4-Dioxothiazolidin-5-
yl)methyl]phenoxy}ethyl 3ꢀ-hydroxyurs-12-en-28-oate
(12)
Compound 12 could be prepared following the procedure
described for 11. White solid, yield 67%, m.p. 127-129 °C.
IR (KBr, ꢁ): 3516, 2939, 1703, 1512; 1H NMR (CDCl3, 300
MHz, ꢅppm): 0.70 (s, 3H), 0.76 (s, 3H), 0.83 (d, 6H, J = 6.2
Hz), 0.94 (s, 3H), 0.97 (s, 3H), 1.06 (s, 3H), 2.24 (d, 1H, J =
10.9 Hz), 3.04-3.12 (m, 1H), 3.18-3.23 (m, 1H), 3.43-3.49
(m, 1H), 4.11 (t, 2H, J = 4.8 Hz), 4.27-4.39 (m, 2H), 4.48
(dd, 1H, J = 3.9, 9.7 Hz), 5.21 (br s, 1H), 6.82-6.85 (m, 2H),
7.12-7.15 (m, 2H); 13C NMR (CDCl3, 75 MHz, ꢅppm):
177.5, 158.2, 138.0, 130.3, 128.1, 125.7, 115.0, 79.1, 66.0,
62.5, 55.2, 53.7, 52.9, 48.2, 47.6, 42.1, 39.6, 39.1, 38.8, 38.7,
38.7, 37.8, 37.0, 36.6, 33.0, 30.7, 28.1, 28.0, 27.2, 24.2, 23.5,
23.3, 21.1, 18.3, 17.1, 17.0, 15.6, 15.4; MS (ESI, m/z):
723.9 [M+NH4]+(50); HRMS for C42H59N1O6S1+Na calcd
728.39608, found 728.39553.
+
(ESI, m/z): 795.5 (M+NH4 , base peak).
Preparation of (S)2-{4-[2-(tert-Butoxycarbonylamino)-2-
carboxyethyl] phenoxy}ethyl 3ꢀ-hydroxyolean-12-en-28-
oate (17)
To a solution of 15 (0.65 g, 0.84 mmol) in MeOH (11.7
mL) and THF (18 mL), 4 M NaOH (5 mL) was added drop-
wise, and the resulting mixture was stirred at room tempera-
ture over night. After neutralized with 1M aqueous solution
of KHSO4, the product was extracted with ethyl acetate (30
mL). The organic phase was washed with water (2 ꢀ 60mL),
dried over Na2SO4 and concentrated. The residue was puri-
fied over a column of silica gel (200-300 mesh) with petro-
leum ether/ethyl acetate 1:1 as eluent to get compound 17 as
white solid 0.27 g, yield 42%, m.p. 133-135 °C. IR (KBr, ꢁ):
3534, 2945, 1725, 1512; 1H NMR (CDCl3, 300 MHz,
ꢅppm): 0.70 (s, 3H), 0.78 (s, 3H), 0.86 (s, 3H), 0.89 (s, 3H),
0.92 (s, 3H), 0.98 (s, 3H), 1.12 (s, 3H), 1.42 (s, 9H), 2.89
(dd, 1H, J = 3.7, 13.8 Hz), 3.03-3.16 (m, 2H), 3.20-3.25 (m,
1H), 4.12 (t, 2H, J = 4.5 Hz), 4.31-4.40 (m, 2H), 4.55 (br s,
1H), 4.93 (br s, 1H), 5.26 (br s, 1H), 6.82 (dd, 2H, J = 8.43,
80.9 Hz), 7.09 (dd, 2H, J = 8.26, 81.1 Hz); 13C NMR
(CDCl3, 75 MHz, ꢅppm): 177.7, 174.9, 157.8, 155.5,
143.6, 130.0, 128.3, 122.5, 114.8, 79.1, 65.9,
62.6, 55.3, 47.6, 46.8, 45.9, 41.7, 41.3, 39.4, 38.8,
38.5, 37.0, 33.9, 33.1, 32.7, 32.4, 30.7, 28.3, 28.1,
27.7, 27.2, 25.9, 23.6, 23.4, 23.0, 18.3, 17.0, 15.6,
15.3; MS (ESI, m/z): 762.6 (M-H-, base peak).
Preparation of (S)-Methyl 3-[4-(2-bromoethoxy)phenyl]-
2-(tert-butoxycarbonylamino)propanoate (14)
A mixture of t-Boc-L-tyrosine methyl ester (0.1 g, 0.34
mmol), 1, 2-dibromoethane (0.2 mL, 2.3 mmol), potassium
carbonate (0.32 g, 2.3 mmol) and 18-crown-6 (0.01 g, 0.04
mmol) was heated at 80 °C for 12 h. After cooling to room
temperature, the mixture was resuspended in ethyl acetate,
filtered and the insoluble substance was washed with ethyl
acetate. The filtrate was concentrated and the residue was
purified over a column of silica gel (200-300 mesh) with
petroleum ether/ethyl acetate 4:1 as eluent to get compound
14 as white solid 0.1 g, yield 70%.
Preparation of (S)2-{4-[2-(tert-Butoxycarbonylamino)-3-
methoxy-3-oxopropyl]phenoxy}ethyl 3ꢀ-hydroxyolean-
12-en-28-oate (15)
Compound 15 could be prepared following the procedure
described for 5. White solid, yield 88%, m.p. 113-115 °C. IR
1
(KBr, ꢁ): 2946, 2854, 1720, 1510; H NMR (CDCl3, 300
MHz, ꢅppm): 0.69 (s, 3H), 0.77 (s, 3H), 0.86 (s, 3H), 0.89
(s, 3H), 0.91 (s, 3H), 0.98 (s, 3H), 1.12 (s, 3H), 1.42 (s, 9H),
2.84 (dd, 1H, J = 4.2, 13.8 Hz), 2.97-3.07 (m, 2H), 3.18-3.23
(m, 1H), 3.71 (s, 3H), 4.12 (t, 2H, J = 4.8 Hz), 4.29-4.42 (m,
2H), 4.51-4.55 (m, 1H), 4.96 (d, 1H, J = 8.5 Hz), 5.26 (t, 1H,
J = 3.3 Hz), 6.80 (dd, 2H, J = 8.6, 64.8 Hz), 7.03 (dd, 2H, J
= 8.5, 64.7 Hz); 13C NMR (CDCl3, 75 MHz, ꢅppm): 177.7,
172.3, 157.7, 143.6, 130.3, 128.4, 122.5, 114.7, 79.0, 65.9,
62.5, 55.2, 52.1, 47.6, 46.8, 45.9, 41.7, 41.3, 39.4, 38.8, 38.5,
37.0, 33.9, 33.1, 32.7, 32.4, 30.7, 28.3, 28.1, 27.7, 27.2, 25.9,
23.6, 23.4, 23.0, 18.3, 17.0, 15.6, 15.3; MS (ESI, m/z):
Preparation of (S)2-{4-[2-(tert-Butoxycarbonylamino)-2-
carboxyethyl] phenoxy}ethyl 3ꢀ-hydroxyurs-12-en-28-
oate (18)
Compound 18 could be prepared following the procedure
described for 17. White solid, yield 38%, m.p. 151-153 °C.
IR (KBr, ꢁ): 3439, 2917, 1723, 1512; 1H NMR (CDCl3, 300
MHz, ꢅppm): 0.72 (s, 3H), 0.77 (s, 3H), 0.85 (d, 6H, J = 8.1
Hz), 0.93 (d, 3H, J = 5.4 Hz), 0.98 (s, 3H), 1.07 (s, 3H), 1.42
(s, 9H), 2.22-2.28 (m, 2H), 3.06-3.17 (m, 2H), 3.19-3.25 (m,
1H), 4.11 (t, 2H, J = 4.6 Hz), 4.31-4.34 (m, 2H), 4.54-4.56
(m, 1H), 4.91-4.94 (m, 1H), 5.23 (br s, 1H), 6.83 (dd, 2H, J
= 8.5, 80.8 Hz), 7.09 (dd, 2H, J = 8.5, 80.7); 13C NMR
+
795.5 (M+NH4 , base peak).