Journal of Medicinal Chemistry
Article
7.67 (m, 4H), 7.36 (m, 6H), 5.21 (t, 1H), 3.20 (m, 1H), 2.23 (d, 1H),
0.81−1.92 (m, 56H). 13C NMR (CDCl3): δ 176.24, 137.79, 135.85,
135.80, 131.99, 129.86, 127.48, 127.45, 125.62, 79.01, 77.31, 77.00,
76.69, 55.17, 53.27, 49.35, 47.53, 42.26, 39.41, 39.36, 38.95, 38.70,
38.65, 36.88, 36.66, 33.21, 30.83, 28.13, 27.89, 27.21, 27.11, 24.72,
23.17, 21.21, 19.33, 18.25, 17.25, 17.05, 15.63, 15.50.
32.09, 30.49, 29.63, 27.92, 25.36, 23.65, 20.80, 19.30, 18.10, 16.48,
16.13, 15.97, 14.63, 14.51.
3β-(Pent-4′-ynoyloxy)olean-12-en-28-oic Acid (OAc). Yield 0.17 g
(95%); mp 199−202 °C. MS (m/z): calcd for C35H52O4, 536. LC-MS
1
(m/z (rel intens)): 536 (M+, 100). H NMR (CDCl3): δ 5.27 (t, J =
3.36 Hz, 1H), 4.53 (t, J = 8.12 Hz, 1H), 2.80 (dd, J = 13.7, 4.2 Hz,
1H), 2.54 (m, 4H), 0.58−1.97 (m, 46H). 13C NMR (CDCl3): δ
183.64, 171.49, 159.63, 145.66, 143.57, 122.51, 82.61, 81.30, 69.01,
56.83, 55.25, 47.49, 46.50, 46.20, 41.52, 40.21, 39.23, 37.92, 37.71,
36.94, 33.82, 33.04, 32.47, 30.64, 28.03, 27.98, 25.89, 23.54, 23.32,
22.89, 18.08, 17.12, 16.68, 15.33, 14.52.
Synthesis of 3 and 11a−b. DIC (5.0 equiv, 0.23 g, 1.8 mmol)
dissolved in dry DCM (4 mL) was added dropwise over 2 min to a
stirred solution of 2 or 10a−b (1.0 equiv, 0.25 g, 0.36 mmol), DMAP
(1.0 equiv, 0.04 g, 0.36 mmol), and pentinoic acid (3.0 equiv, 0.11 g,
1.08 mmol) in dry DCM (6 mL). The mixture was stirred at room
temperature and monitored by TLC. After the reaction was complete,
25 mL of DCM was added, and the organic phase was washed with
10% citric acid, saturated sodium bicarbonate solution, and brine and
dried over Na2SO4. After the mixture was filtered and the filtrate was
evaporated under reduced pressure, the residue was purified by silica
gel column chromatography using petroleum ether/ethyl ether (30:1)
as the eluent to yield 3 and 11a−b as a white solid.
3β-(Pent-4′-ynoyloxy)urs-12-en-28-oic Acid (UAc). Yield 0.16 g
(92%); mp 242−245 °C. MS (m/z): calcd for C35H52O4, 536. LC-MS
1
(m/z (rel intens)): 536 (M+, 100). H NMR (CDCl3): δ 5.24 (t, J =
3.36 Hz, 1H), 4.53 (t, J = 8.16 Hz, 1H), 2.54 (m, 4H), 2.21 (d, J = 7.84
Hz, 1H), 0.77−1.97 (m, 45H). 13C NMR (CDCl3): δ 176.84, 143.36,
122.57, 78.98, 74.36, 55.16, 51.61, 47.57, 46.73, 45.80, 43.85, 41.66,
41.24, 39.33, 38.72, 38.40, 36.99, 33.78, 33.06, 32.70, 32.14, 30.66,
28.06, 27.62, 27.15, 25.81, 23.58, 23.37, 22.97, 18.30, 17.06, 15.55,
15.31.
Synthesis of BAo, OAo, and UAo. To a solution of BA (1.0
equiv, 0.5 g, 1.1 mmol) in 10 mL of DMF were added potassium
carbonate (3.0 equiv, 0.46 g, 3.3 mmol) and propargyl bromide (2.0
equiv, 171 μL, 2.2 mmol). The mixture was stirred at room
temperature for 4 h. The reaction was monitored by TLC. After the
reaction was finished, the remaining potassium carbonate and
generated potassium bromide were removed by filtration, and the
solvent was concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography using ethyl acetate/
petroleum ether (10:1) as the eluent to afford BAo as a white solid.
The above method was used to synthesize compounds OAo and UAo
by using OA and UA instead of BA.
tert-Butyldiphenylsilyl 3β-(Pent-4′-ynoyloxy)lup-20(29)-en-28-
oate (3). Yield 0.21 g (78%); mp 172−174 °C. MS (m/z): calcd for
1
C51H70O4Si, 774. LC-MS (m/z (rel intens)): 797 (M + Na, 7). H
NMR (CDCl3): δ 7.68 (m, 4H), 7.36 (m, 6H), 4.66 (s, 1H), 4.55 (s,
1H), 4.49 (m, 2H), 2.52 (m, 4H), 2.23 (m, 1H), 2.12 (m, 1H), 1.96
(m, 1H), 1.79 (m, 1H), 1.11−1.65 (m, 37H), 0.73−0.94 (m, 19H).
13C NMR (CDCl3): δ 175.21, 171.50, 150.62, 135.39, 135.24, 132.08,
129.93, 127.65, 109.54, 82.64, 81.34, 77.31, 77.00, 76.68, 68.99, 57.71,
55.39, 50.48, 48.90, 46.29, 42.50, 40.69, 38.33, 37.80, 37.72, 37.04,
34.28, 33.81, 32.35, 30.38, 29.85, 27.93, 27.01, 25.48, 23.66, 19.33,
19.29, 18.13, 16.50, 16.23, 15.84, 14.57, 14.51.
tert-Butyldiphenylsilyl 3β-(Pent-4′-ynoyloxy)olean-12-en-28-oate
(11a). Yield 0.22 g (80%); mp 103−105 °C. MS (m/z): calcd for
1
C51H70O4Si, 774. LC-MS (m/z (rel intens)): 775 (M + H, 25). H
Prop-2′-ynyl 3β-Hydroxylup-20(29)-en-28-oate (BAo). Yield 0.42
NMR (CDCl3): δ 7.66 (m, 4H), 7.34 (m, 6H), 5.25 (t, J = 3.08 Hz,
1H), 4.51 (t, J = 9.24 Hz, 1H), 2.87 (d, J = 17.6 Hz, 1H), 2.53 (m,
4H), 0.85−1.97 (m, 67H). 13C NMR (CDCl3): δ176.59, 171.49,
143.59, 135.77, 135.73, 129.88, 127.51, 127.47, 122.25, 82.63, 81.32,
77.31, 77.00, 76.69, 69.00, 55.22, 47.88, 47.44, 46.24, 41.86, 41.60,
39.19, 38.08, 37.69, 36.81, 33.81, 33.06, 30.72, 28.04, 27.08, 25.62,
23.51, 23.34, 19.33, 16.95, 16.73, 15.37, 14.52.
g (78%); mp 185−187 °C. MS (m/z): calcd for C33H50O3, 494. LC-
1
MS (m/z (rel intens)): 495 (M + H, 28). H NMR (CDCl3): δ 4.65
(m, 4H), 3.17 (dd, J = 5.04, 11.52 Hz, 1H), 3.00 (m, 1H), 2.42 (t, J =
2.52 Hz, 1H), 2.19 (m, 2H), 1.90 (m, 2H), 0.73−1.67 (m, 40H). 13C
NMR (CDCl3): δ 175.23, 150.43, 109.64, 78.93, 74.32, 56.54, 55.28,
51.31, 50.50, 49.41, 46.80, 42.33, 40.73, 38.82, 38.65, 38.20, 37.13,
36.76, 34.26, 31.89, 30.44, 29.59, 27.94, 27.34, 25.47, 20.81, 19.33,
18.23, 16.11, 15.96, 15.33, 14.68.
Prop-2′-ynyl 3β-Hydroxyolean-12-en-28-oate (OAo). Yield 0.44 g
(82%); mp 158−160 °C. MS (m/z): calcd for C33H50O3, 494. LC-MS
(m/z (rel intens)): 495 (M + H, 25). 1H NMR (CDCl3): δ 5.30 (t, J =
3.64 Hz, 1H), 4.60 (qd, 2H), 3.22 (m, 1H), 2.85 (m, 1H), 2.41 (t, J =
2.24 Hz, 1H), 1.85−1.98 (m, 3H), 0.74−1.64 (m, 42H). 13C NMR
(CDCl3): δ 176.85, 143.36, 122.57, 78.98, 78.09, 74.37, 55.14, 51.61,
47.55, 46.73, 45.78, 41.65, 41.22, 39.33, 38.72, 38.39, 36.98, 33.77,
33.05, 32.69, 32.14, 30.64, 28.06, 27.62, 27.15, 25.80, 23.57, 23.38,
22.96, 18.29, 17.04, 15.55, 15.32.
Prop-2′-ynyl 3β-Hydroxyurs-12-en-28-oate (UAo). Yield 0.39 g
(80%); mp 145−147 °C. MS (m/z): calcd for C33H50O3, 494. LC-MS
(m/z (rel intens)): 495 (M + H, 18). 1H NMR (CDCl3): δ 5.27 (t, J =
3.64 Hz, 1H), 4.60 (qd, 2H), 3.20 (dd, J = 5.04, 10.64 Hz, 1H), 2.42
(t, J = 2.52 Hz, 1H), 2.25 (d, J = 10.9 Hz, 1H), 2.03 (m, 1H), 1.89 (m,
2H), 1.31−1.69 (m, 18H), 0.76−1.08 (m, 25H). 13C NMR (CDCl3):
δ 176.66, 137.70, 125.82, 78.99, 78.06, 74.39, 55.14, 52.76, 51.57,
48.13, 47.49, 42.00, 39.54, 39.02, 38.73, 38.58, 36.91, 36.38, 32.99,
30.58, 28.09, 27.97, 27.18, 24.14, 23.45, 23.25, 21.15, 18.26, 17.15,
16.97, 15.61, 15.45.
Synthesis of BApc, OApc, and UApc. To a solution of BA, OA,
or UA (1.0 equiv, 1.0 g, 2.0 mmol) in 10 mL of DMF were added
potassium carbonate (2.0 equiv, 0.61 g, 4.0 mmol) and allyl bromide
(1.6 equiv, 284 μL, 3.3 mmol). The mixture was stirred at room
temperature for 4 h. The reaction was monitored by TLC. After the
reaction was finished, the remaining potassium carbonate and
generated potassium bromide were removed by filtration, and the
solvent was concentrated under reduced pressure. The product was
directly used for the next step without further purification. In the next
step, DIC (6.0 equiv, 0.23 g, 1.8 mmol) dissolved in dry DCM (4 mL)
tert-Butyldiphenylsilyl 3β-(Pent-4′-ynoyloxy)urs-12-en-28-oate
(11b). Yield 0.18 g (68%); mp 98−99 °C. MS (m/z): calcd for
1
C51H70O4Si, 774. LC-MS (m/z (rel intens)): 775 (M + H, 57). H
NMR (CDCl3): δ 7.66 (m, 4H), 7.34 (m, 6H), 5.20 (t, J = 3.64 Hz,
1H), 2.53 (m, 4H), 2.25 (d, J = 10.9 Hz, 1H), 1.96 (m, 2H), 1.76 (m,
5H), 0.83−1.56 (m, 47H). 13C NMR (CDCl3): δ 176.25, 171.48,
137.83, 135.85, 135.80, 132.00, 129.86, 127.48, 127.45, 125.48, 82.63,
81.33, 77.31, 77.00, 76.68, 69.00, 55.24, 53.25, 49.34, 47.44, 42.25,
39.41, 39.35, 38.94, 38.28, 37.68, 36.76, 33.81, 30.82, 28.08, 27.87,
27.11, 24.71, 23.54, 23.20, 23.14, 21.21, 19.33, 17.23, 17.08, 15.79,
15.54, 14.52.
Synthesis of BAc, OAc, and UAc. Under enclosed conditions
flushed with N2, tetrabutylammonium fluoride (TBAF) (1.5 equiv,
0.14 g, 0.52 mmol) was added to a solution of 3 (1.0 equiv, 0.27 g,
0.34 mmol) in 5 mL of THF. The mixture was stirred for 3 h at room
temperature with monitoring by TLC. After the reaction was
complete, 15 mL of DCM was added. The organic phase was washed
with 1 M HCl and brine and dried over Na2SO4. After the mixture was
filtered and the filtrate was evaporated under reduced pressure, the
residue was purified by silica gel column chromatography using
petroleum ether/ethyl acetate (8:1) as the eluent to yield BAc as a
white solid. The same procedure described above was used to obtain
OAc and UAc from 11a−b.
3β-(Pent-4′-ynoyloxy)lup-20(29)-en-28-oic Acid (BAc). Yield 0.16
g (90%); mp 253−255 °C. MS (m/z): calcd for C35H52O4, 535. LC-
1
MS (m/z (rel intens)): 536 (M+, 100). H NMR (CDCl3): δ 4.73 (s,
1H), 4.61 (s, 1H), 4.50 (m, 1H), 2.53 (m, 4H), 2.25 (m, 2H), 1.96 (m,
2H), 0.83−1.69 (m, 41H). 13C NMR (CDCl3): δ 181.75, 181.62,
171.55, 150.38, 109.73, 82.63, 81.33, 69.01, 56.31, 55.34, 50.30, 49.17,
46.90, 42.36, 40.62, 38.33, 38.24, 37.80, 37.05, 36.99, 34.15, 33.79,
J
dx.doi.org/10.1021/jm500763m | J. Med. Chem. XXXX, XXX, XXX−XXX