Journal of Natural Products
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completion (3.5 h for 23, 9 h for 24). Saturated aqueous NH4Cl
solution (50 mL) was added, the CH2Cl2 phase was separated, and the
aqueous layer was extracted with EtOAc (2 × 70 mL). The organic
layers were combined, dried over MgSO4, and concentrated in vacuo
to afford pure ester 23 as a white solid and 24 as a colorless oil.
(E)-Methoxymethyl 3-[3-methoxy-4-(methoxymethoxy)phenyl]-
acrylate (23): 8.17 g (29.0 mmol, 96%), white microcrystalline
solid; mp 46 °C; UV (MeOH) λmax 233, 294, 320 nm; 1H NMR (300
MHz, CDCl3) δ ppm 7.68 (d, J = 15.9 Hz, 1H), 7.15 (d, J = 8.5 Hz,
1H), 7.12−7.03 (m, 2H), 6.33 (d, J = 15.9 Hz, 1H), 5.35 (s, 2H), 5.26
(s, 2H), 3.91 (s, 3H), 3.50 (s, 3H), 3.50 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ ppm 166.4, 149.7, 148.6, 145.4, 128.5, 122.3, 115.73, 115.65,
110.3, 95.1, 90.4, 57.6, 56.3, 55.8; EIMS m/z 282 [M]+• (19), 176
(24), 146 (12); HREIMS m/z 282.1108 [M]+• (calcd for C14H18O6
282.1103).
115.7, 110.5, 95.1, 56.4, 55.9; EIMS m/z 222 [M]+• (23), 192 (6), 161
(7); HREIMS m/z 222.0889 [M]+• (calcd for C12H14O4, 222.0892).
(E)-3-[4-(Methoxymethoxy)phenyl]acrylaldehyde (28): 3.45 g
1
(17.9 mmol, 73%), yellow oil; UV (MeOH) λmax 230, 313 nm; H
NMR (300 MHz, CDCl3) δ ppm 9.64 (d, J = 7.7 Hz, 1H), 7.50 (d, J =
8.6 Hz, 2H), 7.41 (d, J = 15.9 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.60
(dd, J = 15.9, 7.7 Hz, 1H), 5.21 (s, 2H), 3.47 (s, 3H); 13C NMR (75
MHz, CDCl3) δ ppm 193.6, 159.7, 152.5, 130.2 (2C), 127.7, 126.8,
116.5 (2C), 94.0, 56.2; EIMS m/z 192 [M]+• (21), 131 (5); HREIMS
m/z 192.0788 [M]+• (calcd for C11H12O3 192.0786).
Aldol Condensations toward 29 and 30.25 Aldehydes 27 (2.10
g, 9.47 mmol) and 28 (388 mg, 2.02 mmol) in a cooled (0 °C)
acetone−H2O solution (7:1) were mixed with a 10% (w/w) NaOH
aqueous solution (0.5 equiv) and stirred at room temperature for 16 h.
Subsequently, the solution was neutralized with 1 M aqueous HCl, and
after addition of H2O (50 mL) the aqueous solution was extracted
with EtOAc (3 × 70 mL). After drying over MgSO4 and removal of
EtOAc, the crude product was purified with CC (SiO2; petroleum
ether, bp 40−60 °C−EtOAc, 3:1), yielding pure 29 and 30 as yellow
solids.
(E)-Methoxymethyl 3-[4-(methoxymethoxy)phenyl]acrylate (24):
6.20 g (24.6 mmol, 99%), yellowish oil; UV (MeOH) λmax 225, 306
1
nm; H NMR (300 MHz, CDCl3) δ ppm 7.68 (d, J = 16.0 Hz, 1H),
7.46 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 16.0 Hz,
1H), 5.33 (s, 2H), 5.18 (s, 2H), 3.49 (s, 3H), 3.45 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ ppm 166.5, 159.0, 145.1, 129.7 (2C), 127.9, 116.4
(2C), 115.4, 94.0, 90.3, 57.5, 56.0; ESIMS m/z 253 [M + H]+ (6), 191
[M + H − CH3OCH2OH]+ (100), 145 (23); HRESIMS m/z
253.1068 [M + H]+ (calcd for C13H17O5 253.1071).
(3E,5E)-6-[3-Methoxy-4-(methoxymethoxy)phenyl]hexa-3,5-dien-
2-one (29): 1.71 g (6.54 mmol, 69%), yellow solid; mp 77 °C; UV
(MeOH) λmax 254, 350 nm; 1H NMR (400 MHz, CDCl3) δ ppm 7.27
(dd, J = 15.9, 10.3 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02−6.98 (m,
2H), 6.88 (d, J = 15.5 Hz, 1H), 6.76 (dd, J = 15.5, 10.5 Hz, 1H), 6.23
(d, J = 15.5 Hz, 1H), 5.24 (s, 2H), 3.92 (s, 3H), 3.50 (s, 3H), 2.30 (s,
3H); 13C NMR (75 MHz, CDCl3) δ ppm 198.5, 149.8, 147.7, 143.7,
141.1, 130.4, 129.8, 125.2, 121.1, 115.9, 109.6, 95.2, 56.3, 55.9, 27.3;
ESIMS m/z 263 [M + H]+ (100); HRESIMS m/z 263.1276 [M + H]+
(calcd for C15H19O4, 263.1278).
(3E,5E)-6-[4-(Methoxymethoxy)phenyl]hexa-3,5-dien-2-one (30):
333 mg (1.44 mmol, 71%), yellow solid; mp 60−62 °C; UV (MeOH)
λmax 241, 340 nm; 1H NMR (300 MHz, CDCl3) δ ppm 7.42 (d, J = 8.7
Hz, 1H), 7.28 (dd, J = 15.5, 10.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H),
6.91 (d, J = 15.6 Hz, 1H), 6.77 (dd, J = 15.5, 10.6 Hz, 1H), 6.23 (d, J =
15.5 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H), 2.31 (s, 3H); 13C NMR (75
MHz, CDCl3) δ ppm 198.5, 158.1, 143.9, 140.9, 129.8, 129.7, 128.7
(2C), 125.0, 116.5 (2C), 94.2, 56.1, 27.3; ESIMS m/z 233 [M + H]+
(100); HRESIMS m/z 233.1170 [M + H]+ (calcd for C14H17O3,
233.1172).
Formation of Allylic Alcohols 25 and 26 by Reduction of α,β-
Unsaturated Esters 23 and 24.23 The ester 23 (7.58 g, 26.9 mmol)
or 24 (6.53 g, 24.9 mmol) was dissolved under N2 atmosphere in dry
THF (0.2 M) and cooled to −78 °C. LiAlH4 (1.6 equiv) was added in
portions, and the mixture stirred until conversion was complete (30
min to 1 h). The unreacted LiAlH4 was slowly quenched with MeOH
until gas evolution stopped, followed by addition of H2O (200 mL).
The aqueous slurry was neutralized with 1 M aqueous HCl and
subsequently extracted with EtOAc (2 × 200 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure to yield pure allylic alcohols 25 and 26 as yellowish oils.
(E)-3-[3-Methoxy-4-(methoxymethoxy)phenyl]prop-2-en-1-ol
(25): 5.77 g (25.8 mmol, 96%), yellowish oil; UV (MeOH) λmax 259
1
nm; H NMR (300 MHz, CDCl3) δ ppm 7.08 (d, J = 8.3 Hz, 1H),
6.94 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.3, 2.0 Hz, 1H), 6.54 (d, J =
15.9 Hz, 1H), 6.24 (dt, J = 15.8, 5.8 Hz, 1H), 5.21 (s, 2H), 4.29 (dd, J
= 5.8, 1.4 Hz, 2H), 3.88 (s, 3H), 3.50 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ ppm 149.7, 146.2, 131.3, 130.9, 127.1, 119.5, 116.2, 109.3,
95.4, 63.7, 56.2, 55.8; ESIMS m/z 247 [M + Na]+ (27), 207 [M + H −
H2O]+ (67), 175 [M + H − H2O − MeOH]+ (100); HRESIMS m/z
247.0940 [M + Na]+ (calcd for C12H16NaO4 247.0941).
(E)-3-[4-(Methoxymethoxy)phenyl]prop-2-en-1-ol (26): 4.79 g
(24.7 mmol, 99%), yellowish oil; UV (MeOH) λmax 261 nm; 1H
NMR (300 MHz, CDCl3) δ ppm 7.31 (d, J = 8.7 Hz, 1H), 6.99 (d, J =
8.8 Hz, 1H), 6.56 (dd, J = 15.9, 7.3 Hz, 1H), 6.24 (dt, J = 15.8, 5.9 Hz,
1H), 5.17 (s, 1H), 4.29 (dd, J = 5.9, 1.4 Hz, 2H), 3.47 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ ppm 156.6, 130.5, 130.3, 127.5 (2C),
126.8, 116.2 (2C), 94.2, 63.4, 55.9; ESIMS m/z 217 [M + Na]+ (3),
177 [M + H − H2O]+ (17), 145 [M + H − H2O − MeOH]+ (100);
HRESIMS m/z 177.0911 [M + H − H2O]+ (calcd for C11H13O2
177.0910).
Hydrogenation of Unsaturated Ketones to Ketones 31 and
32.26 The unsaturated ketones 29 (1.66 g, 6.34 mmol) and 30 (316
mg, 1.36 mmol) were dissolved in CHCl3 (0.15 M) and 10% (w/w)
Pd/C (10% Pd on charcoal), and Ph2S (0.05 equiv) was added. The
mixture was stirred under a H2 atmosphere, and after 24 h, Pd/C was
filtered off using a pad of Celite and the solvent removed in vacuo. The
crude product was purified by CC (SiO2; petroleum ether, bp 40−60
°C−EtOAc, 2:1), yielding 31 and 32 as colorless oils.
6-[3-Methoxy-4-(methoxymethoxy)phenyl]hexan-2-one (31):
1.33 g (4.96 mmol, 78%), colorless oil; UV (MeOH) λmax 223, 277
1
nm; H NMR (300 MHz, CDCl3) δ ppm 7.04 (d, J = 8.0 Hz, 1H),
6.71 (d, J = 1.8 Hz, 1H), 6.68 (dd, J = 8.0, 1.9 Hz, 1H), 5.18 (s, 2H),
3.86 (s, 3H), 3.50 (s, 3H), 2.56 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 6.8 Hz,
2H), 2.12 (s, 3H), 1.65−1.54 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
ppm 209.0, 149.5, 144.4, 136.7, 120.3, 116.5, 112.0, 95.6, 56.1, 55.8,
43.5, 35.4, 31.0, 29.9, 23.4; ESIMS m/z 235 [M + H − CH3OH]+, 284
[M + NH4]+; HRESIMS m/z 266.1505 [M]+· (calcd for C15H22O4
266.1513).
Oxidation of Alcohols 25 and 26 to Aldehydes 27 and 28.23
The allylic alcohol 25 (5.72 g, 23.5 mmol) or 26 (4.74 g, 24.4 mmol)
was dissolved in CH2Cl2 (0.1 M) and stirred with 18 equiv of MnO2
for 48 h. The black slurry was filtered through a pad of Celite while
being eluted with CH2Cl2. After the evaporation of the solvent, the
residue was purified with flash chromatography (SiO2; n-hexane−
EtOAc, 4:1; 50 mL min−1), affording 27 as a yellow solid and 28 as a
yellow oil.
3-[3-Methoxy-4-(methoxymethoxy)phenyl]acrylaldehyde (27):
3.58 g (16.1 mmol, 69%), mp 67−69 °C; UV (MeOH) λmax 236,
330 nm; 1H NMR (300 MHz, CDCl3) δ ppm 9.59 (d, J = 7.7 Hz, 1H),
7.35 (d, J = 15.8 Hz, 1H), 7.18−6.97 (m, 3H), 6.55 (dd, J = 15.8, 7.7
Hz, 1H), 5.21 (s, 2H), 3.85 (s, 3H), 3.44 (s, 3H); 13C NMR (100
MHz, CDCl3) δ ppm 193.5, 152.6, 149.9, 149.4, 128.3, 127.1, 123.0,
6-[4-(Methoxymethoxy)phenyl]hexan-2-one (32): 268 mg (1.14
1
mmol, 83%), colorless oil; UV (MeOH) λmax 220, 273 nm; H NMR
(300 MHz, CDCl3) δ ppm 7.07 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7
Hz, 2H), 5.13 (s, 2H), 3.45 (s, 3H), 2.55 (t, J = 7.1 Hz, 2H), 2.42 (t, J
= 6.9 Hz, 2H), 2.10 (s, 3H), 1.68−1.49 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ ppm 208.8, 155.2, 135.4, 129.1 (2C), 116.0 (2C), 94.4, 55.7,
43.4, 34.7, 30.9, 29.7, 23.2; EIMS m/z (%) 236 [M]+• (19), 151 (8),
121 (31); HREIMS 236.1414 [M]+· (calcd for C14H20O3 236.1412).
MOM Protection of Vanillin and 4-Hydroxybenzaldehyde to
35 and 36.22 To a stirred solution of vanillin (33) (10.0 g, 65.7
mmol) or benzaldehyde 34 (10.0 g, 81.9 mmol) in CH2Cl2 (0.8 M) at
0 °C were added DIPEA (1.6 equiv) and MOM chloride (1.3 equiv),
H
dx.doi.org/10.1021/np500396y | J. Nat. Prod. XXXX, XXX, XXX−XXX