Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction
6
H), 0.76 (s, 3H).
(α)-hydroxylup-28-oic acid (8) Compound 8 was
-1.17 (m, other aliphatic ring protons), 1.13-1.05 (m,
3
1H), 1.02 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.84 (s, 3H),
1
13
synthesized using general procedure B. Yield: 94%. H
NMR (500 MHz, CDCl ) δ: 4.74 (d, J=2.5 Hz, 1H),
.61 (m, 1H), 3.39 (t, J=3.0 Hz, 1H), 3.01 (td, J=11.0,
.0 Hz, 1H), 2.27 (dt, J=13.0, 3.5 Hz, 1H), 2.18 (td,
0.77 (s, 3H); C NMR (125 MHz, CDCl
3
) δ: 212.38,
3
181.18, 78.89, 56.13, 55.22, 51.18, 50.30, 49.18, 42.19,
40.70, 40.53, 38.79, 38.54, 37.45, 37.15, 36.68, 34.06,
31.42, 30.09, 29.66, 28.26, 27.94, 27.29, 20.81, 18.21,
4
5
J=12.5, 3.5 Hz, 1H), 2.03-1.87 (m, 3H), 1.69 (s, 3H),
.61 (t, J=11.5 Hz, 1H), 1.55-1.27 (m, other aliphatic
ring protons), 0.99 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H),
16.07, 15.92, 15.33, 14.68. HRMS (ESI): calcd for
+
1
C
29
H
47
O
4
[M+H] 459.3474, found 459.2440.
3(β)-Hydroxy-20(29)-epoxylup-28-oic acid (13)
13
1
0
.84 (s, 3H), 0.82 (s, 3H); C NMR (125 MHz, CDCl
3
)
3
Yield: 80.4%. H NMR (500 MHz, CDCl ) δ: 3.20 (dd,
δ: 181.35, 150.43, 109.67, 76.27, 56.38, 50.26, 49.26,
J=11.5, 5.0 Hz, 1H), 2.68-2.62 (m, 2H), 2.27 (dt, J=
13.0, 3.5 Hz, 1H), 2.20-2.07 (m, 2H), 2.03-1.88 (m,
2H), 1.82-1.29 (m, other aliphatic ring protons), 1.25
4
3
2
9.04, 46.94, 42.50, 40.87, 38.37, 37.52, 37.32, 37.05,
4.16, 33.24, 32.16, 30.57, 29.65, 28.25, 25.46, 25.37,
2.08, 20.69, 19.35, 18.23, 16.03, 15.91, 14.77. HRMS
(s, 3H), 1.00-0.96 (s, 6H), 0.93 (s, 3H), 0.84 (s, 3H),
+
13
(ESI): calcd for C30
H
49
O
3
[M+H] 457.3682, found
0.76 (s, 3H); C NMR (125 MHz, CDCl
3
) δ: 179.20,
4
57.2779.
78.97, 60.07, 56.55, 55.32, 50.38, 49.93, 45.35, 42.43,
40.70, 38.86, 38.73, 37.54, 37.19, 36.87, 34.32, 32.01,
29.69, 29.44, 27.98, 27.37, 26.99, 26.84, 20.93, 18.30,
1
3
(α)-Oleanic acid (9) Yield: 60.6% for 4 steps. H
NMR (500 MHz, CDCl
3
1
3
) δ: 5.28 (t, J=3.5 Hz, 1H),
.41 (t, J=3.0 Hz, 1H), 2.86-2.75 (m, 1H), 2.03-
.92 (m, 2H), 1.89 (dd, J=9.0, 3.5 Hz, 2H), 1.80-1.16
18.28, 16.11, 16.00, 15.35, 14.59. HRMS (ESI): calcd
+
for C30
H
48
O
4
Na [M+Na] 495.3450, found 495.3440.
(
m, other aliphatic ring protons), 1.14 (s, 3H), 1.07 (dt,
3(β)(29)-Dihydroxylupan-28-oic acid (14) Yield:
45.3%. H NMR (500 MHz, CD OD) δ: 3.74 (dd, J=
3
10.5, 4.5 Hz, 1H), 3.14 (dd, J=11.5, 5.0 Hz, 1H), 2.36
-2.27 (m, 2H), 2.23 (dt, J=12.5, 3.5 Hz, 1H), 1.81 (dd,
J=12.0, 7.5 Hz, 2H), 1.76-1.70 (m, 1H), 1.66-1.27
(m, other aliphatic ring protons), 1.17 (dt, J=13.5, 3.0
1
J=14.0, 3.5 Hz, 1H), 0.95 (s, 3H), 0.92 (s, 6H), 0.90 (s,
13
3
H), 0.83 (s, 3H), 0.75 (s, 3H); C NMR (125 MHz,
CDCl ) δ: 183.45, 143.57, 122.66, 76.18, 48.96, 47.39,
6.51, 45.86, 41.63, 40.92, 39.42, 37.32, 37.15, 33.79,
3
4
3
2
3.06, 32.83, 32.45 (2*C), 30.66, 28.27, 27.61, 26.09,
5.16, 23.58, 23.30, 22.91, 22.24, 18.22, 17.17, 15.10+.
Hz, 1H), 1.01 (s, 3H), 0.99-0.95 (m, 9H), 0.88 (s, 3H),
13
HRMS (ESI): calcd for C30
79.3501, found 479.3482.
(α)-Ursolic acid (10) Yield: 67.6% for 4 steps. H
NMR (500 MHz, CDCl ) δ: 5.24 (t, J=4.0 Hz, 1H),
.41 (t, J=3.0 Hz, 1H), 2.21-2.14 (m, 1H), 2.03-
.22 (m, other aliphatic ring protons),1.09 (s, 3H), 0.96
0.93 (m, 9H), 0.85 (d, J=6.5 Hz, 3H), 0.83 (s, 3H),
H
48
O
3
Na [M + Na]
0.76 (s, 3H); C NMR (125 MHz, CD
3
OD) δ: 179.92,
4
79.46, 64.01, 57.60, 56.65, 51.59, 49.54, 44.47, 43.53,
41.75, 39.90, 39.76, 39.45, 39.28, 38.12, 38.10, 35.48,
32.98, 30.68, 28.42, 28.26, 27.85, 24.52, 22.03, 19.26,
1
3
3
3
1
-
0
1
3
3
2
18.54, 16.50 (2*C), 15.93, 14.87. HRMS (ESI): calcd
+
51 4
for C30H O [M+H] 475.3787, found 475.3250.
3(α)-Hydroxylupan-28-oic acid (15) To a stirred
solution of 7 (150 mg, 0.27 mmol) in MeOH (10 mL),
Pd/C (15 mg) was added at ambient temperature under
nitrogen atmosphere. The nitrogen atmosphere was re-
1
3
3
.77 (s, 3H); C NMR (125 MHz, CDCl ) δ: 182.77,
37.87, 125.87, 76.15, 52.57, 48.94, 47.93, 47.32, 42.00,
9.63, 39.03, 38.82, 37.33, 37.05, 36.72, 33.05, 32.78,
0.61, 28.28, 27.94, 25.19, 24.10, 23.73, 23.17, 22.26,
placed by the H
stirred for 24 h at room temperature, then H
2
atmosphere. The reaction mixture was
was re-
1.18, 18.20, 17.10, 16.98, 15.25. HRMS (ESI): calcd
2
+
for C30
H
48
O
3
Na [M+Na] 479.3501, found 479.3499.
placed with nitrogen and the mixture was filtered
through Celite and washed with DCM. The residue was
concentrated and purified by flash chromatography.
Yield: 98 mg (0.21 mmol, 79%). H NMR (500 MHz,
3
CDCl ) δ: 3.40 (t, J=3.0 Hz, 1H), 2.28-2.14 (m, 3H),
Compounds 11-14 were synthesized according to
[10]
the previous reference.
(β)-Hydroxylupan-28-oic acid (11) Yield: 86%.
H NMR (500 MHz, CDCl ) δ: 3.19 (dd, J=11.5, 5.0
Hz, 1H), 2.26-2.17 (m, 3H), 1.91-1.77 (m, 2H), 1.71
1.15 (m, other aliphatic ring protons), 0.97 (s, 3H),
.95 (s, 3H), 0.93 (s, 3H), 0.85 (d, J=6.9 Hz, 3H), 0.83
1
3
1
3
1.98-1.90 (m, 1H), 1.87 (dd, J=12.5, 7.5 Hz, 1H),
1.80 (m, 1H), 1.67-1.14 (m, other aliphatic ring pro-
tons), 0.97 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H), 0.87-
-
0
13
13
(
s, 3H), 0.77-0.73 (m, 6H); C NMR (125 MHz,
CDCl ) δ: 179.64, 78.97, 56.67, 55.30, 50.27, 48.73,
4.12, 42.58, 40.69, 38.85, 38.70, 38.20, 37.36, 37.17,
0.84 (m, 6H), 0.82 (s, 3H), 0.76 (d, J=6.5 Hz, 3H); C
3
3
NMR (125 MHz, CDCl ) δ: 181.47, 76.27, 56.80, 50.02,
4
3
2
49.01, 48.75, 44.17, 42.64, 40.87, 38.21, 37.52, 37.40,
37.29, 34.23, 33.24, 32.06, 29.71, 29.63, 28.24, 26.89,
25.36, 22.98, 22.73, 22.09, 20.72, 18.23, 16.07, 15.87,
4.39, 32.06, 29.70, 29.68, 27.98, 27.36, 26.89, 22.97,
2.70, 21.05, 20.87, 18.28, 16.08, 15.35, 14.66, 14.59+.
HRMS (ESI): calcd for C30
H
50
O
3
Na [M + Na]
14.68 (2*C). HRMS (ESI): calcd for C30
H
50
O
3
Na [M+
+
4
81.3658, found 481.2624.
(β)-Hydroxy-20-ketolup-28-oic acid (12) Yield:
Na] 481.3658, found 481.3640.
3
Benzyl 3(α)-hydroxylupan-28-oate (16)
Com-
1
4
2
3.6%. H NMR (500 MHz, CDCl
3
) δ: 3.31-3.19 (m,
pound 16 was synthesized using general procedure A.
1
H), 2.33-2.26 (m, 1H), 2.20 (s, 3H), 2.15 (t, J=11.0
Yield: 95%. H NMR (300 MHz, CDCl
3
) δ: 7.35 (m,
Hz, 1H), 2.12-2.05 (m, 1H), 2.05-1.96 (m, 1H), 1.73
5H), 5.10-5.07 (m, 2H), 3.38 (s, 1H), 2.28-2.24 (m,
Chin. J. Chem. 2016, XX, 1—10
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3