Journal of Natural Products
Article
37.0, 33.9, 32.9, 31.9, 30.7, 29.7, 29.2, 27.2, 25.7, 25.5, 23.7, 23.5,
23.4, 19.0, 17.3, 16.7, 14.9; ESIMS m/z 485 (M + H)+.
175.4, 144.6, 123.6, 86.4, 55.2, 47.2, 46.1, 45.5, 42.2, 40.8, 40.0, 39.4,
37.4, 33.9, 32.96, 32.91, 31.99, 31.92, 30.7, 27.1, 25.5, 25.4, 23.9, 23.6,
23.4, 22.6, 20.8, 16.5, 16.4; ESIMS m/z 486 (M + H)+.
3-Hydroxyimino-N-hydroxyurs-12-en-28-amide (4d): pale yellow
solid (70%); IR (KBr) 2956, 2833, 1729, 1630, 1423, 1390, 1374,
A-seco-4,12-dienolean-N-hydroxy-3-amide-28-methyl ester (12):
982, 949 cm−1; H NMR (300 MHz, CDCl3) δ 5.40 (1H, brt), 3.07
prepared from 11b23 after KOH hydrolysis and hydroxyamidation
1
1
(1H, brt, J = 15.6), 2.12 (1H, m), 1.24 (3H, s), 1.15 (3H, s), 1.08
(3H, s), 1.06 (3H, s), 1.03 (3H, s), 0.94 (3H, s), 0.81 (3H, s) (only
readily peaks are reported); 13C NMR (75 MHz, CDCl3) δ 177.3,
167.7, 140.6, 126.5, 55.7, 52.1, 47.0, 42.5, 40.2, 39.6, 39.4, 39.0, 38.5,
37.0, 36.7, 32.2, 30.6, 29.7, 27.7, 27.4, 24.8, 23.5, 23.4, 23.3, 21.1,
19.0, 17.3, 17.2, 16.8, 15.1; ESIMS m/z 485 (M + H)+.
3-Hydroxyimino-N-hydroxylup-20(29)-en-28-amide (5d): off-
white solid (65%); IR (KBr) 2966, 2831, 1751, 1715, 1665, 1453,
1449, 1034, 1007, 984, 866 cm−1; 1H NMR (300 MHz, CO(CD3)2) δ
4.73 (1H, s), 4.61 (1H, d, J = 6.1 Hz), 3.04−3.00 (2H, m), 2.32 (1H,
s), 1.68 (3H, s), 1.24 (6H, s), 1.22 (3H, s), 1.12 (3H, s), 0.97 (3H, s),
0.96 (3H, s), 0.91 (3H, s) (only readily peaks are reported); 13C
NMR (75 MHz, CO(CD3)2) δ 176.7, 164.1, 150.5, 109.6, 56.0, 55.5,
55.3, 50.2, 47.1, 42.5, 40.8, 40.2, 38.7, 38.2, 37.9, 37.2, 34.0, 33.3,
30.8, 29.4, 27.4, 25.6, 22.9, 21.5, 21.2, 19.4, 19.1, 16.1, 15.8, 14.6;
ESIMS m/z 485 (M + H)+.
according to protocol A. White solid (20%): H NMR (300 MHz,
CDCl3) δ 5.29 (1H, brt), 4.85 (1H, s), 4.66 (1H, s), 3.62 (3H, s),
2.74 (1H, brdd, J = 9.7 Hz), 1.71 (3H, s), 1.10 (3H, s), 0.90 (6H, s),
0.87 (6H, s), 0.74 (3H, s) (only readily observed peaks are reported);
13C NMR (75 MHz, CDCl3) δ 178.4, 171.9, 147.5, 143.7, 122.2,
113.7, 60.54, 51.6, 50.8, 46.8, 45.8, 42.2, 41.4, 39.3, 39.1, 38.1, 33.9,
33.1, 32.4, 31.4, 30.7, 27.7, 25.8, 24.4, 23.6, 21.1, 20.8, 19.4, 18.4,
16.9, 14.2; ESIMS m/z 500 (M + H)+.
Heterocyclic Hydroxamates. Synthesis of 14a as an example:
(a) Formylation: To a solution of 5c (300 mg, 0.65 mmol) in toluene
(70 mL) were sequentially added NaOEt (221 mg, 3.25 mmol, 5
molar equiv) and ethyl formate (241 mg, 3.25 mmol, 5 molar equiv).
The reaction mixture was stirred at 50 °C overnight, quenched with 2
N H2SO4, and extracted with EtOAc. The organic phases were
washed with brine, dried over Na2SO4, and evaporated at reduced
pressure to afford 2-formyl-3-oxobetulinic acid28 as a colorless oil,
which was used without further purification for the next step. (b) 1,2-
Diazole formation (reaction with hydroxylammonium chloride as an
example): To a stirred solution of crude 2-formyl-3-oxo-betulinic acid
(310 mg, 0.64 mmol, 1 molar equiv) in ethanol/H2O, 9:1 (6 mL),
was added hydroxylammonium chloride (400 mg, 5.76 mmol, 9 molar
equiv). The reaction mixture was heated at 80 °C for 5 h, diluted with
H2O, and extracted with EtOAc. The organic phases were washed
with brine, dried over Na2SO4, and evaporated at reduced pressure,
affording the crude product as a brown oil, used without further
purification. (c) Hydroxyamidation: The reaction was carried out
according to protocol A, affording compound 14a (41% from 5c) as a
white powder.
Lup-2-eno[2,3-d]-isoxazol-N-hydroxy-28-amide (14a): white
powder; IR (KBr) 2953, 2867, 1714, 1632, 1508, 1455, 1367, 956,
887 cm−1; 1H NMR (300 MHz, CD3OD) δ 10.37 (1H, s, NH), 8.42
(1H, s, OH), 8.26 (1H, s), 4.67 (1H, s), 4.55 (1H, s), 3.00 (1H, t, J =
9.3 Hz), 2.61 (1H, t, J = 12.0 Hz), 1.64 (3H, s), 1.40 (3H, s), 1.22
(3H, s), 1.11 (3H, s), 0.93 (3H, s), 0.74 (3H, s) (only readily
observed peaks are reported); 13C NMR (75 MHz, CDCl3) δ 172.6,
151.3, 151.0, 109.9, 109.4, 54.0, 53.3, 50.6, 49.0, 48.9, 46.7, 42.4, 38.9,
37.3, 35.6, 34.8, 33.4, 32.6, 30.9, 29.0, 25.7, 21.7, 19.5, 18.7, 16.4,
16.2, 14.8; ESIMS m/z 495 (M + H)+.
Synthesis of Δ2-Hydroxamates. Synthesis of 9 as an example:
To a stirred solution of oleanolic acid (3a, 500 mg, 1.1 mmol, 1 molar
equiv) in dry pyridine (9 mL) was added p-toluenesulfonyl chloride
(735 mg, 3.8 mmol, 3.8 molar equiv). The solution was stirred at
room temperature for 24 h under a nitrogen atmosphere, diluted with
water, and then extracted with CH2Cl2. The organic phases were
washed with saturated KHSO4 solution, dried over Na2SO4, and
concentrated at reduced pressure. The crude product was diluted in
DMF (6 mL), sodium acetate (315 mg, 2.3 mmol) was added, and
the mixture was heated at 120 °C for 24 h under a nitrogen
atmosphere. The mixture was diluted with brine and extracted with
CH2Cl2. The organic phases were dried over Na2SO4 and evaporated.
The residue was purified over silica gel (petroleum ether/EtOAc,
9:1), affording 221 mg (42%) of Δ2-oleanolic acid,27 diluted in dry
CH2Cl2 (4 mL), and cooled at 0 °C. Oxalyl chloride (249 μL, 2.9
mmol, 6 molar equiv) was then added dropwise, and the mixture was
heated at 40 °C for 1.5 h. The solvent was then removed at reduced
pressure, the residue dissolved in dry pyridine, and hydroxylammo-
nium chloride (201 mg, 2.9 mmol, 6 molar equiv) added. The
reaction was heated at 40 °C for 3 h, quenched with 2 N H2SO4, and
extracted with EtOAc. The organic phases were washed with brine,
dried over Na2SO4, and evaporated at reduced pressure. The crude
reaction product was purified over silica gel (petroleum ether/EtOAc,
7:3), affording 104 mg (48%) of 9 as a yellowish oil: IR (KBr) 2949,
1′H-Lup-20(29)-eno[3,2-c]-pyrazol-N-hydroxy-28-amide (14b):
yellowish powder (overall 48% from 5a); IR (KBr) 2986, 2798,
1
1700, 1655, 1508, 1390, 1287, 1035, 851, 739 cm−1; H NMR (300
1
2868, 1632, 1461, 1387, 1362, 910, 731 cm−1; H NMR (300 MHz,
MHz, (CD3)2CO) δ 7.17 (1H, s), 4.72 (1H, s), 4.58 (1H, s), 3.17
(1H, s), 2.65 (1H, s), 1.69 (3H, s), 1.28 (3H, s), 1.18 (3H, s), 1.02
(3H, s), 0.98 (3H, s), 0.80 (3H, s) (only readily observed peaks are
reported); 13C NMR (75 MHz, (CD3)2CO) δ 172.4, 151.0, 149.1,
132.8, 111.9, 109.0, 59.7, 50.0, 53.7, 50.5, 49.2, 46.8, 42.2, 40.7, 38.6,
37.9, 37.7, 36.6, 33.5, 33.4, 32.3, 30.8, 30.6, 25.7, 23.3, 21.4, 19.1,
18.7, 15.6, 14.2, 13.7; ESIMS m/z 494 (M + H)+.
2-(28-Oleanoylamido)-3-(2-hydroxyphenyl)acrylic acid (15b). In
a sealed tube, a solution of oleanoylglycineamide (15a,24 200 mg, 0.39
mmol) in acetic anhydride (92 μL, 0.97 mmol, 2.5 molar equiv) was
treated with salicylic aldehyde (72 mg, 0.58 mmol, 1.5 molar equiv)
and NaOAc (24 mg, 0.29 mmol, 0.75 molar equiv). The reaction was
heated at 140 °C for 1.5 h, then diluted with MeOH, EtOAc, and
brine. The organic phases were dried over Na2SO4 and evaporated at
reduced pressure. The crude azalactone (154 mg, 0.26 mmol) was
dissolved in THF/MeOH, 1:1 (4 mL), and 4 N NaOH (5 mL, 20
mmol; 51 molar equiv). The mixture was heated at 40 °C overnight,
quenched with 2 N H2SO4, and extracted with EtOAc. The organic
phases were washed with brine, dried over Na2SO4, and evaporated at
reduced pressure. The crude product was purified over silica gel
(petroleum ether/EtOAc, 9:1, as eluant), affording 82 mg (35% from
15a) of 15b as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.76
(1H, s), 8.70 (1H, s), 7.35 (3H, m), 5.63 (1H, brt), 3.18 (1H, dd, J =
7.9, 1.5 Hz), 2.73 (1H, dd, J = 11.4, 0.9 Hz), 1.18 (3H, s), 0.95 (3H,
CDCl3) δ 5.43−5.32 (3H, m), 2.44 (1H, d, J = 11.3 Hz), 1.14 (3H,
s), 0,97 (6H, s), 0.87 (12H, s) (only readily peaks are reported); 13C
NMR (75 MHz, CDCl3) δ 176.4, 144.5, 138.0, 124.1, 121.3, 51.9,
46.4, 46.1, 45.5, 42.1, 41.0, 40.7, 39.5, 36.1, 34.5, 34.0, 33.0, 31.9,
31.8, 31.6, 30.7, 27.2, 25.9, 25.7, 23.8, 23.5, 22.9, 19.6, 16.3, 15.6;
ESIMS m/z 454 (M + H)+.
Lupa-2,20(29)-diene-N-hydroxy-28-amide (10): yellowish powder
(54%); IR (KBr) 2936, 2868, 1717, 1643, 1448, 1374, 881, 731 cm−1;
1H NMR (300 MHz, CDCl3) δ 5.38−5.28 (2H, m), 4.69 (1H, s),
4.56 (1H, s), 3.01 (1H, t, J = 10.7 Hz), 2.37 (1H, t, J = 12.1 Hz), 1.63
(3H, s), 1.21 (3H, s), 0.93 (3H, s), 0,89 (3H, s), 0.82 (3H, s), 0.81
(3H, s) (only readily observed peaks are reported); 13C NMR (75
MHz, CDCl3) δ 175.0, 150.5, 137.9, 121.6, 109.65, 54.3, 52.1, 50.4,
49.2, 42.3, 40.8, 38.4, 37.9, 36.4, 34.6, 33.5, 32.8, 31.7, 30.9, 30.8,
29.7, 29.3, 25.6, 22.6, 19.5, 16.4, 15.8, 14.6, 14.5, 14.3; ESIMS m/z
454 (M + H)+.
Triterpenoid Hydroxamates from the Products of Bayer−
Villiger Fragmentation (11a, 11b). Olean-12-ene-N-hydroxy-28-
amid-3-oic acid ε-lactone (13): prepared from 11a23 according to
the hydroxyamidation protocol A. White solid (35%); 1H NMR (300
MHz, CDCl3) δ 5.45 (1H, brt), 2.63 (2H, t, J = 5.4 Hz), 2.47 (1H,
brdd, J = 9.4 Hz), 2.05 (2H, m), 1.52 (3H, s), 1.46 (3H, s), 1.29 (3H,
s), 1.16 (3H, s), 0.90 (3H, s), 0.88 (6H, s), 0.83 (3H, s) (only readily
observed peaks are reported); 13C NMR (75 MHz, CDCl3) δ 176.5,
G
J. Nat. Prod. XXXX, XXX, XXX−XXX