Journal of Natural Products
Article
quench the reaction, and the resultant liquid mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography using a
prepacked 25 g silica column [solvent A: EtOAc; solvent B: hexanes;
gradient: 7% A/93% B (1 CV), 7% A/93% B → 60% A/40% B (10
CV), 60% A/40% B (2 CV); flow rate: 75 mL/min; monitored at 254
and 280 nm], yielding CA1-BAPC 26 (0.020 g, 0.037 mmol, 13%) as
an orange oil: 1H NMR (600 MHz, CDCl3) δ 7.80 (1H, d, J = 4.2 Hz,
ArH), 7.01 (1H, d, J = 8.7 Hz, ArH), 6.93 (1H, d, J = 4.3 Hz, ArH),
6.58 (1H, d, J = 12.1 Hz, CH), 6.49 (2H, s, ArH), 6.47 (1H, d, J = 8.6
Hz, ArH), 6.45 (1H, d, J = 12.1 Hz, CH), 4.60 (1H, sept, J = 6.0 Hz,
CH), 3.82 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.66 (6H, s, OCH3),
1.71 (6H, s, CH3), 1.23 (6H, d, J = 6.1 Hz, CH3); 13C NMR (151
MHz, CDCl3) δ 161.4, 154.6, 152.8, 151.6, 150.4, 137.1, 137.0, 132.7,
129.0, 128.1, 126.4, 126.2, 125.3, 122.1, 106.4, 105.9, 81.7, 75.1, 60.9,
55.8, 55.5, 28.8, 22.4; HRMS m/z 566.1819 [M + Na]+ (calcd for
NaC28H33NO8S+, 566.1819); HPLC (method B) 22.3 min, 91%, 4.9%
parent (isopropyl-protected CA1 analogue 21), 0% CA1.
gradient: 5% A/95% B (1 CV), 5% A/95% B → 40% A/60% B (10
CV), 40% A/60% B (2 CV); flow rate: 75 mL/min; monitored at 254
and 280 nm].
(Z)-tert-Butyl(6-methoxy-2-((5-nitrothiophen-2-yl)methoxy)-3-
(3,4,5-trimethoxystyryl)phenoxy)dimethylsilane (30). This isomer
30 (0.350 g, 0.739 mmol, 35%) was isolated as a brownish-yellow oil:
1H NMR (600 MHz, CDCl3) δ 7.76 (1H, d, J = 4.1 Hz, ArH), 6.91
(1H, d, J = 4.1 Hz, ArH), 6.87 (1H, dd, J = 8.6, 0.8 Hz, ArH), 6.57
(1H, d, J = 8.6 Hz, ArH), 6.50 (1H, d, J = 12.0 Hz, CH), 6.45 (1H, d,
J = 12.2 Hz, CH), 6.44 (2H, s, ArH), 5.12 (2H, s, CH2), 3.82 (3H, s,
OCH3), 3.79 (3H, s, OCH3), 3.65 (6H, s, OCH3), 0.99 (9H, s,
C(CH3)3), 0.13 (6H, s, Si(CH3)2); 13C NMR (126 MHz, CDCl3) δ
152.7, 151.6, 151.4, 148.6, 147.6, 138.4, 137.1, 132.4, 130.4, 128.2,
125.1, 124.9, 124.4, 122.3, 107.5, 105.9, 68.5, 60.9, 55.8, 55.4, 25.8,
18.6, −4.6.
(Z)-tert-Butyl(3-methoxy-2-((5-nitrothiophen-2-yl)methoxy)-6-
(3,4,5-trimethoxystyryl)phenoxy)dimethylsilane (33). Isomer 33
(0.250 g, 0.425 mmol, 25%) was isolated as a brownish-yellow oil:
1H NMR (600 MHz, CDCl3) δ 7.81 (1H, d, J = 4.1 Hz, ArH), 7.00
(1H, d, J = 8.7 Hz, ArH), 6.96 (1H, d, J = 4.1 Hz, ArH), 6.56 (1H, d,
J = 12.2 Hz, CH), 6.52 (2H, s, ArH), 6.44 (1H, d, J = 11.6 Hz, CH),
6.42 (1H, d, J = 8.5 Hz, ArH), 5.30 (2H, s, CH2), 3.83 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 3.67 (6H, s, OCH3), 1.01 (9H, s,
C(CH3)3), 0.18 (6H, s, Si(CH3)2); 13C NMR (151 MHz, CDCl3) δ
153.4, 152.8, 152.7, 148.8, 147.8, 138.4, 137.0, 132.6, 129.1, 128.2,
126.3, 125.9, 125.4, 123.3, 105.9, 104.9, 68.8, 60.9, 55.9, 55.8, 26.1,
18.6, −3.9.
Synthesis of Compounds 31 and 34. Mono-TBS CA1 [mixture of
27 and 28 (0.680 g, 1.52 mmol)], diisopropylazodicarboxylate (0.415
g, 2.05 mmol), and 1-(5-nitrothiophen-2-yl)ethan-1-ol (0.317 g, 1.82
mmol) were dissolved in THF (50 mL). Triphenylphosphine (0.793
g, 3.04 mmol) was added, and the reaction mixture was stirred (3 d).
The reaction mixture was concentrated under reduced pressure, and
the residue was purified by flash column chromatography using a
prepacked 50 g silica column [solvent A: EtOAc; solvent B: hexanes;
gradient: 5% A/95% B (1 CV), 5% A/95% B → 40% A/60% B (13
CV), 40% A/60% B (2 CV); flow rate: 80 mL/min; monitored at 254
and 280 nm].
Synthesis of Compounds 27, 28, and 29. Deprotection of the
TBS group of compound 13 using TBAF (0.9 equiv) yielded an
inseparable mixture of compounds 27 and 28. At the same time,
about 15% CA1 (compound 29) was also isolated.
(Z)-2-((tert-Butyldimethylsilyl)oxy)-3-methoxy-6-(3,4,5-
trimethoxystyryl)phenol (27) and (Z)-2-((tert-butyldimethylsilyl)-
oxy)-6-methoxy-3-(3,4,5-trimethoxystyryl)phenol (28).43,44 To a
solution of di-TBS CA1 13 (2.00 g, 3.57 mmol) in THF (150 mL)
at −15 °C was added dropwise TBAF·3H2O (1.01 g, 3.20 mmol)
dissolved in THF (10 mL). The reaction was stirred for 0.5 h. H2O
was used to quench the reaction, THF was removed by evaporation,
and the residue was extracted with EtOAc (3 × 30 mL). The
combined extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography using a prepacked 100 g silica
column [solvent A: EtOAc; solvent B: hexanes; gradient: 5% A/95%
B (1 CV), 5% A/95% B → 70% A/30% B (13 CV), 70% A/30% B (2
CV); flow rate: 100 mL/min; monitored at 254 and 280 nm],
affording a mixture of compounds 27 and 28 (0.860 g, 2.59 mmol,
43%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 6.80 (1H, d, J
= 8.7 Hz, ArH), 6.71 (1H, d, J = 8.7 Hz, ArH), 6.58 (2H, d, J = 12.0
Hz, CH), 6.52 (4H, s, ArH), 6.47 (1H, d, J = 12.1 Hz, CH), 6.41
(1H, d, J = 12.2 Hz, CH), 6.36 (1H, d, J = 8.5 Hz, ArH), 6.30 (1H, d,
J = 8.6 Hz, ArH), 5.66 (1H, s, OH), 5.45 (1H, s, OH), 3.81 (6H, s,
OCH3), 3.78 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.64 (12H, d, J =
2.2 Hz, OCH3), 1.01 (9H, d, J = 5.2 Hz, C(CH3)3), 1.00 (9H, s,
C(CH3)3), 0.22 (6H, s, Si(CH3)2), 0.19 (6H, s, Si(CH3)2); 13C NMR
(126 MHz, CDCl3) δ 152.7, 152.7, 149.3, 146.9, 145.9, 141.2, 137.0,
137.0, 136.8, 132.9, 132.8, 131.6, 129.6, 129.0, 126.8, 124.5, 123.2,
122.0, 120.1, 117.1, 106.1, 106.0, 103.8, 103.0, 60.9, 60.8, 56.1, 55.8,
55.7, 55.2, 26.0, 26.0, 18.6, 18.6, −3.9, −4.4.
(Z)-tert-Butyl(6-methoxy-2-(1-(5-nitrothiophen-2-yl)ethoxy)-3-
(3,4,5-trimethoxystyryl)phenoxy)dimethylsilane (31). Isomer 31
1
(0.375 g, 0.623 mmol, 41%) was isolated as a yellow oil: H NMR
(600 MHz, CDCl3) δ 7.60 (1H, d, J = 4.2 Hz, ArH), 6.76−6.69 (2H,
m, ArH), 6.41 (1H, d, J = 8.2 Hz, ArH), 6.39 (1H, d, J = 11.9 Hz,
CH), 6.32 (2H, s, ArH), 6.29 (1H, d, J = 12.1 Hz, CH), 5.58 (1H, q, J
= 6.4 Hz, CH), 3.69 (3H, s, OCH3), 3.65 (3H, s, OCH3), 3.51 (6H, s,
OCH3), 1.48 (3H, d, J = 6.4 Hz, CH3), 0.85 (9H, s, C(CH3)3), 0.00
(3H, s, Si(CH3)), −0.02 (3H, s, Si(CH3)); 13C NMR (151 MHz,
CDCl3) δ 155.0, 152.7, 151.4, 150.9, 146.1, 138.5, 137.2, 132.4, 129.8,
128.1, 125.6, 124.9, 123.4, 122.5, 107.0, 106.0, 74.4, 60.9, 55.8, 55.3,
25.8, 22.3, 18.6, −4.3, −4.4.
(Z)-3-Methoxy-6-(3,4,5-trimethoxystyryl)benzene-1,2-diol (29).
Combretastatin A-1 29 (0.179 mg, 0.538 mmol, 15%) was isolated
as a white solid: 1H NMR (500 MHz, CDCl3) δ 6.76 (1H, d, J = 8.6
Hz, ArH), 6.59 (1H, d, J = 12.1 Hz, CH), 6.54 (1H, d, J = 11.9 Hz,
CH), 6.52 (2H, s, ArH), 6.39 (1H, d, J = 8.6 Hz, ArH), 5.39 (2H, s,
OH), 3.86 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.67 (6H, s, OCH3);
13C NMR (126 MHz, CDCl3) δ 152.9, 146.5, 141.7, 137.4, 132.7,
(Z)-tert-Butyl(3-methoxy-2-(1-(5-nitrothiophen-2-yl)ethoxy)-6-
(3,4,5-trimethoxystyryl)phenoxy)dimethylsilane (34). Isomer 34
1
(0.073 g, 0.122 mmol, 12%) was isolated as a yellow oil: H NMR
(600 MHz, CDCl3) δ 7.61 (1H, d, J = 4.2 Hz, ArH), 6.84 (1H, d, J =
8.7 Hz, ArH), 6.71 (1H, d, J = 4.2 Hz, ArH), 6.38 (1H, d, J = 12.0 Hz,
CH), 6.37 (2H, s, ArH), 6.26 (1H, d, J = 12.3 Hz, CH), 6.24 (1H, d, J
= 8.6 Hz, ArH), 5.26 (1H, q, J = 6.5 Hz, CH), 3.67 (3H, s, OCH3),
3.61 (3H, s, OCH3), 3.50 (6H, s, OCH3), 1.47 (3H, d, J = 6.5 Hz,
CH3), 0.84 (9H, s, C(CH3)3), 0.03 (3H, s, Si(CH3)), 0.00 (3H, s,
Si(CH3)); 13C NMR (151 MHz, CDCl3) δ 153.3, 151.1, 150.9, 149.1,
146.1, 135.5, 135.2, 130.7, 126.9, 126.2, 124.6, 123.7, 121.5, 121.5,
104.1, 103.0, 73.1, 59.0, 53.9, 24.2, 24.2, 19.8, 16.7, −5.2, −5.7.
(Z)-tert-Butyl(6-methoxy-2-((2-(5-nitrothiophen-2-yl)propan-2-
yl)oxy)-3-(3,4,5-trimethoxystyryl)phenoxy)dimethylsilane (32).
Mono-TBS CA1 [mixture of 27 and 28, (1.07 g, 2.40 mmol)], gem-
dimethyl trigger 19 (0.540 g, 2.88 mmol), and ADDP (0.832 g, 3.30
mmol) were dissolved in CH2Cl2 (100 mL). Tributylphosphine (1.26
mL, 5.04 mmol) was added dropwise, and the reaction mixture was
stirred (2 d). The reaction mixture was then concentrated under
132.6, 130.5, 124.2, 120.5, 118.0, 106.1, 103.1, 76.9, 61.0, 56.3, 56.0;
+
HRMS m/z 355.1154 [M + Na]+ (calcd for NaC18H20O6 ,
355.1152); HPLC (method A) 11.3 min, 99%.
Synthesis of Compounds 30 and 33. To a mixture of compounds
27 and 28 (1.00 g, 2.24 mmol), nor-methyl trigger 16 (0.428 g, 2.69
mmol), and DIAD (0.867 mL) in CH2Cl2 (50 mL) was added
dropwise PPh3 (1.47 g, 5.60 mmol). The reaction mixture was stirred
(24 h) at room temperature. H2O (40 mL) was added to quench the
reaction, and the resultant liquid mixture was extracted with CH2Cl2
(3 × 20 mL). The combined extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography using a
prepacked 25 g silica column [solvent A: EtOAc; solvent B: hexanes;
L
J. Nat. Prod. XXXX, XXX, XXX−XXX