Journal of Natural Products
Article
saturated NaHCO3 (100 mL) was added. Et2O was used for
extraction, and the organic layers were washed with brine and dried
over MgSO4. The solvent was removed in vacuo, and the residue was
purified by flash chromatography using EtOAc and hexane to afford 4
128.5, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 127.2, 124.6, 114.6,
106.9, 105.4, 104.2, 100.0, 70.4, 70.1, 68.8, 66.1, 55.4, 55.4, 48.1, 37.8,
26.0, 18.3; HRESIMS m/z 796.3276 [M + Na]+ (calcd for
C46H51NNaO8Si 796.3286).
1
(11.05 g, 86%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ
MOM-Protected Alcohol 8. MOMCl (2.00 mL) was added
dropwise to alcohol 7 (5.96 g, 7.70 mmol) and DIPEA (4.34 mL)
in anhydrous CH2Cl2 (50 mL) at 0 °C, and the mixture was warmed
to rt overnight. After TLC indicated the reaction was not complete,
additional amounts of MOMCl (2.00 mL) and DIPEA (4.34 mL) were
added, and stirring was continued overnight. H2O was added, and the
mixture was stirred for 10 min, extracted with CH2Cl2, and washed
with brine. Flash chromatography (hexane−EtOAc 9:1) gave 8 (5.23
g, 83%) as a light yellow oil: [α]D23 +77.4 (c 0.09, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.59 (1H, d, J = 8.0 Hz), 7.44 (2H, d, J = 8.0
Hz), 7.36−7.26 (8H, m), 7.24−7.19 (4H, m), 7.00 (2H, dd, J = 7.2,
1.2 Hz), 6.54 (2H, td, J = 9.0, 2.4 Hz), 6.45 (1H, d, J = 2.4 Hz), 6.25
(1H, d, J = 2.4 Hz), 6.04 (1H, d, J = 8.8 Hz), 5.63 (1H, d, J = 8.8 Hz),
5.04−4.96 (2H, m), 4.94 (2H, s), 4.45 (1H, d, J = 8.8 Hz), 4.36 (1H,
d, J = 8.8 Hz), 4.17−4.11 (1H, m), 3.75 (3H, s), 3.71 (2H, dd, J = 8.8,
2.4 Hz), 3.46 (1H, t, J = 8.0 Hz), 3.09 (1H, dd, J = 13.2 Hz, 3.2 Hz),
3.03 (3H, s), 2.11 (1H, dd, J = 13.2, 10.4 Hz), 1.05 (9H, s), 0.22 (6H,
d, J = 2.8 Hz); 13C NMR (101 MHz, CDCl3) δ 171.8, 159.8, 159.0,
158.1, 154.6, 152.2, 137.2, 136.9, 135.9, 130.1, 129.9, 129.3, 128.7,
128.5, 128.3, 127.9, 127.5, 127.5, 127.4, 126.9, 122.8, 118.0, 107.1,
104.9, 104.5, 99.9, 94.1, 71.9, 70.4), 69.9, 65.4, 55.9, 55.6, 55.2, 46.8,
37.3, 34.6, 25.8, 18.2; HRESIMS m/z 840.3528 [M + Na]+ (calcd for
C48H55NNaO9Si 840.3544).
9.67 (1H, s), 7.37−7.29 (5H, m), 7.05 (1H, d, J = 8.0 Hz), 6.55 (1H,
s), 6.48 (1H, d, J = 8.0 Hz), 5.04 (2H, s), 3.77 (3H, s), 3.61 (2H, s);
13C NMR (100 MHz, CDCl3) δ 200.3, 160.4, 157.5, 136.5, 131.6,
128.6, 127.9, 127.2, 127.2, 113.7, 104.8, 99.9, 70.1, 55.3, 44.8;
HRESIMS m/z 257.7738 [M + H]+ (calcd for C16H17O3 257.7718).
2-Benzyloxy-4-methoxyphenylacetic Acid (5). At 0 °C, NaH2PO4
(6.21 g, 51.7 mmol) in 40 mL of H2O was added to aldehyde 4 (11.05
g, 43.1 mmol), 2-methyl-2-butene (18.14 g, 258.7 mmol), and NaClO2
(tech. 80%, 5.85 g, 51.74 mmol) in t-BuOH/THF (1:1, 200 mL). The
ice bath was removed after 30 min, and the mixture was stirred for 3 h.
The organic solvents were removed in vacuo, and the aqueous layer
was extracted with CH2Cl2 and then dried over MgSO4. After solvent
was evaporated, the crude compound was purified by recrystallization
from EtOAc−hexane to give compound 5 (9.50 g, 81%) as a white
1
solid: mp 114.0−116 °C; H NMR (400 MHz, CDCl3) δ 7.35−7.26
(5H, m), 7.10 (1H, d, J = 8.0 Hz), 6.50 (1H, d, J = 2.4 Hz), 6.46 (1H,
dd, J = 8.0, 2.4 Hz), 3.76 (3H, s), 3.63 (2H, s); 13C NMR (100 MHz,
CDCl3) δ 177.6, 160.2, 157.3, 136.6, 131.3, 128.5, 127.8, 127.0, 115.1,
104.6, 99.9, 70.0, 55.3, 35.2; HRESIMS m/z 273.1120 [M + H]+
(calcd for C16H17O4 273.1127).
Imide 6. To a solution of acid 5 (10.64 g, 39.1 mmol) in anhydrous
CH2Cl2 (100 mL) were added oxalyl chloride (7 mL) and DMF
(catalytic). The mixture was then stirred at rt for 1 h, followed by
evaporation of solvent. The residue was dissolved in anhydrous THF
to give an acyl chloride solution. In another flask, n-BuLi (2.5 M, 16.4
mL, 41 mmol) was added to (R)-4-benzyl-2-oxazolidinone (7.09 g, 40
mmol) in anhydrous THF (160 mL) at −78 °C. The mixture was
warmed to 0 °C, stirred for an additional 30 min, and then recooled to
−78 °C. The acyl chloride solution was added dropwise to the reaction
mixture and stirred at the same temperature for 1 h before being
warmed to rt and stirred for 2 h. Saturated aqueous NH4Cl was added,
and the mixture was extracted with EtOAc, which was washed with
brine, dried over MgSO4, and triturated with EtOAc and hexane to
Alcohol 9. LiBH4 (4 M in THF, 2.00 mL) was added to alcohol 8
(5.23 g, 6.40 mmol) in aqueous Et2O (50 mL, plus 0.1 mL H2O) at rt,
and the mixture was stirred for 1 h. The reaction was quenched with 1
N NaOH (30 mL) and stirred for an additional 1 h. The solution was
extracted with Et2O, washed with brine, and dried over Mg2SO4. Flash
chromatography (hexane−EtOAc 4:1) gave 9 (2.51 g, 61%) as a
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1
colorless oil: [α]D +141.5 (c 0.07, MeOH); H NMR (400 MHz,
CDCl3) δ 7.42−7.29 (11H, m), 7.00 (1H, d, J = 8.4 Hz), 6.50 (2H, dt,
J = 8.8, 2.4 Hz), 6.39 (1H, d, J = 2.4 Hz), 6.34 (1H, d, J = 2.4 Hz), 5.42
(1H, d, J = 6.4 Hz), 4.98 (2H, s), 4.93 (1H, d, J = 12.4 Hz), 4.81 (1H,
d, J = 12.4 Hz), 4.40 (2H, dd, J = 16.4 Hz, 8.4 Hz), 3.81−3.78 (2H,
m), 3.75 (3H, s), 3.73−3.71 (1H, m), 3.13 (3H, s), 1.01 (9H, s), 0.18
(6H, d, J = 4.4 Hz); 13C NMR (100 MHz, CDCl3) δ 159.3, 158.8,
158.1, 154.5, 137.5, 137.1, 129.8, 129.2, 128.7, 128.5, 128.1, 127.7,
127.6, 127.3, 123.7, 120.9, 107.8, 105.7, 104.8, 100.1, 94.2, 72.1, 70.3,
70.2, 64.5, 55.6, 55.4, 44.8, 29.9, 26.0, 18.4; HRESIMS m/z 667.3055
[M + Na]+ (calcd for C38H48NaO7Si 667.3067).
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give 6 (13.3 g, 79%) as a white solid: mp 108.0−110.0 °C; [α]D
1
−52.2 (c 0.12, MeOH); H NMR (400 MHz, CDCl3) δ 7.40−7.25
(8H, m), 7.13−7.09 (3H, m), 6.55 (1H, d, J = 2.4 Hz), 6.50 (1H, dd, J
= 8.0 Hz, 2.4 Hz), 5.03 (2H, s), 4.54−4.48 (1H, m), 4.22 (2H, d, J =
2.8 Hz), 4.04 (1H, dd, J = 8.8 Hz, 2.8 Hz), 3.97 (1H, t, J = 8.0 Hz),
3.79 (3H, s), 3.19 (1H, dd, J = 13.4 Hz, 2.8 Hz), 2.47 (1H, dd, J = 13.4
Hz, 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.5, 160.2, 157.4,
153.5, 136.9, 135.5, 131.5, 129.3, 128.8, 128.8, 128.5, 127.9, 127.4,
127.1, 115.7, 104.5, 99.8, 70.8, 66.1, 55.4, 55.3, 37.6, 36.8; HRESIMS
m/z 432.1817 [M + H]+ (calcd for C26H26NO5 432.1811).
Diol 10. To a solution of alcohol 9 (2.51 g, 3.89 mmol) in THF (20
mL) was added tetrabutylammonium fluoride (TBAF) (1 M in THF,
5 mL). After 1 h, water was added, and EtOAc was used for extraction.
The organic layers were combined, washed with brine, and dried over
MgSO4. Flash chromatography (hexane−EtOAc 1:1) gave diol 10
Alcohol 7. To a stirred solution of imide 6 (7.56 g, 17.52 mmol) in
anhydrous CH2Cl2 (100 mL) was added N,N-diisopropylethylamine
(DIPEA) (3.70 mL, 21 mmol) and dibutylboron triflate (1 M in
CH2Cl2, 20 mL) at −78 °C. The mixture was warmed to 0 °C and
stirred for 1 h. The aldehyde 1 (6.60 g, 19.27 mmol) in anhydrous
CH2Cl2 was added dropwise, and the resultant mixture was stirred at
−78 °C for 1 h. The reaction was warmed to rt, stirred overnight, and
quenched by addition of pH 7 buffer (25 mL), followed by slow
addition of MeOH−H2O (2:1, 50 mL) with ice bath cooling followed
by further stirring at rt for 1 h. The organic solvent was removed under
vacuum, and Et2O was used for extraction. The organic layers were
washed with saturated NaHCO3 and dried over MgSO4. Flash
chromatography (hexane−EtOAc 9:1) gave 7 (10.3 g, 76%) as a white
solid: mp 74.0−76.0 °C; [α]D23 +70.3 (c 0.15, MeOH); 1H NMR (400
MHz, CDCl3) δ 7.39−7.24 (13H, m), 7.11−7.09 (3H, m), 6.76 (1H,
d, J = 8.0 Hz), 6.41 (2H, ddd, J = 15.6, 8.4, 2.4 Hz), 6.30 (1H, d, J =
2.4 Hz), 6.12 (1H, d, J = 2.4 Hz), 5.59 (2H, s), 4.92 (2H, s), 4.81 (1H,
d, J = 12.0 Hz), 4.64−4.58 (1H, m), 4.53 (1H, d, J = 12.0 Hz), 3.96−
3.95 (2H, m), 3.71 (3H, s), 3.67 (1H, d, J = 2.4 Hz), 3.28 (1H, dd, J =
13.4 Hz, 2.8 Hz), 2.42 (1H, dd, J = 13.4 Hz, 10.0 Hz), 0.94 (9H, s),
0.13 (6H, s); 13C NMR (100 MHz, CDCl3) δ 175.2, 160.2, 158.7,
158.6, 153.2, 152.1, 137.5, 137.4, 135.6, 131.2, 129.6, 129.1, 128.7,
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1
(1.99 g, 96%) as a colorless oil: [α]D +188.0 (c 0.08, MeOH); H
NMR (400 MHz, CDCl3) δ 7.41−7.30 (10H, m), 7.20 (1H, d, J = 8.4
Hz), 6.85 (1H, d, J = 8.4 Hz), 6.53−6.48 (3H. m), 6.42 (1H, dd, J =
8.4, 2.4 Hz), 5.15 (1H, d, J = 8.4 Hz), 5.00−4.98 (4H, m), 4.54 (1H, d,
J = 6.8 Hz), 4.37 (1H, d, J = 6.8 Hz), 3.76 (3H, s), 3.67−3.62 (3H, m),
2.96 (3H, s); 13C NMR (100 MHz, CDCl3) δ 159.8, 159.7, 157.8,
156.7, 136.9, 136.6, 129.7, 128.6, 128.5, 128.0, 127.9, 127.6, 127.5,
120.4, 116.8, 106.9, 104.7, 103.4, 100.1, 94.1, 70.4, 69.9, 63.4, 55.8,
55.3; HRESIMS m/z 553.2188 [M + Na]+ (calcd for C32H34NaO7
553.2202).
Ether 11. To diol 10 (1.99 g, 3.73 mmol) and PPh3 (1.18 g, 4.50
mmol) in 30 mL of anhydrous THF was added DEAD (40 wt % in
toluene, 2.10 mL, 4.60 mmol), and TLC indicated the reaction was
complete after about 30 min. The mixture was loaded onto silica gel
and purified by flash chromatography (hexane−EtOAc 1:1) to give
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ether 11 (1.83 g, 96%) as a colorless oil: [α]D −21.5 (c 0.13,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.46−7.29 (10H, m), 7.14
(1H, d, J = 8.4 Hz), 7.04 (1H, d, J = 8.4 Hz), 6.57 (1H, dd, J = 8.4 Hz,
2.4 Hz), 6.50 (2H, dd, J = 9.6 Hz, 2.4 Hz), 6.32 (1H, dd, J = 8.4 Hz,
2.4 Hz), 5.08 (2H, s), 5.01 (2H, s), 4.70−4.68 (2H, m), 4.62 (1H, d, J
= 8.4 Hz), 4.47 (1H, dd, J = 11.2 Hz, 3.2 Hz), 4.45 (1H, dd, J = 11.2,
D
J. Nat. Prod. XXXX, XXX, XXX−XXX