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JOURNAL OF CHEMICAL RESEARCH 2014 379
evaporated under reduced pressure and the residue was triturated with
petroleum ether repeatedly to provide 35.91 g (99%) of HCl⋅L-Ser-
OCH3 (5) as a colourless powder which was used directly for the next
reaction.
and K2CO3 in acetone for 6 h, vanillin was transformed to
the allyl ether 3 in 98% yield. It was then converted to the
phenol derivative 4 via a Dakin oxidation reaction. L-serine
methyl ester hydrochloride (5) was prepared from L-serine
quantitatively by refluxing with SOCl2 in methanol. It was then
acylated and dehydrated by reacting with (E)-methyl 4-chloro-
4-oxobut-2-enoate generated from monomethyl fumarate in
situ.
(E)-Methyl 4-(1-methoxy-1-oxoprop-2-en-2-ylamino)-4-oxobut-2-
en-oate (6): Under argon, thionyl chloride (0.20 mL, 2.90 mmol) was
added to monomethyl fumarate (37.3 mg, 0.29 mmol) in a 10 mL round-
bottomed flask and then heated to reflux for 2 h. The reaction mixture
was then evaporated to remove excessive thionyl chloride to give the
acyl chloride, which was used directly for the next step. Under argon, a
three-necked flask equipped with a dropping funnel was charged with
5 (44.6 mg, 0.29 mmol) and anhydrous CH2Cl2 (5 mL). Et3N (0.28 mL)
in CH2Cl2 (2 mL) were added at 0 °C, followed by the dropwise addition
of the acyl chloride in CH2Cl2 (5 mL). The reaction mixture was stirred
30 min at 0 °C and overnight at room temperature. Water (10 mL) are
added to the flask, and, after separation, the organic phase was washed
with water (2×10 mL) and brine (2×10 mL) then dried over MgSO4.
The suspension was filtered and the solvent removed under vacuum.
Flash chromatography (PE: AcOEt=5: 1) afforded 6 (37.1 mg, 60%).
1H NMR δ (CDCl3, ppm, 400 MHz): 3.82 (s, 3H), 3.88 (s, 3H), 6.01 (s,
1H), 6.76 (s, 1H), 6.89 (d, J=15.6 Hz, 1H), 6.99 (d, J=15.6 Hz, 1H), 8.05
(brs, 1H, NH).
(E)-Methyl-4-(5-(allyloxy)-6-methoxy-3-methyl-2-oxo-2,3-
dihydrobenzofuran-3-ylamino)-4-oxobut-2-en-oate (7): BF3⋅Et2O
(0.4 mL, 1.38 mmol) was added to a solution of 4 (99 mg, 0.55 mmol)
and 6 (117 mg, 0.55 mmol) in anhydrous THF (2 mL). The mixture
was then heated to reflux for 48 h. Work-up began by quenching with
saturated NaHCO3 aqueous solution followed by filtration. The solvent
was removed under reduced pressure and the residue was extracted
with CH2Cl2. The combined organic extracts were washed with brine
(20 mL), dried over Na2SO4 and concentrated under reduced pressure.
Flash chromatography (PE: acetone=4: 1→3: 1) afforded 7 as a white
solid (99.4 mg, 50%). 1H NMR δ (CDCl3, ppm, 600 MHz): 1.68 (s, 3H),
3.78 (s, 3H), 3.87 (s, 3H), 4.53 (m, 2H), 5.26 (d, J=10.8 Hz, 1H), 5.38 (d,
J=16.8 Hz, 1H), 6.03–6.07 (m, 1H), 6.75 (d, J=15.6 Hz, 1H), 6.78 (s,
1H), 6.81 (s, 1H), 6.91 (d, J=15.6 Hz, 1H), 7.44 (brs, 1H, NH), 13C NMR
δ (CDCl3, ppm): 176.2, 166.0, 162.8, 151.5, 147.7, 145.5, 134.4, 133.2,
131.5, 119.0, 118.1, 108.8, 96.6, 71.1, 57.8, 56.3, 52.4, 24.1.
A
cascade Friedel–Crafts alkylation/lactonisation with
intermediates 4 and 6 gave benzofuranone 7, which was then
smoothly converted to 8 by refluxing in DMF. Isomerisation
of the terminal double bond was carried out by our previous
method.7 When 8 was heated under reflux for 8 h in the
presence of RhCl3·3H2O in ethanol, the olefin isomerisation
took place accompanied by transesterification to give
(±)-methoxyfumimycin ethyl ester (9).
Conclusions
In conclusion, we have developed a concise synthetic route
to (±)-methoxyfumimycin ethyl ester by a convergent and
protecting-group-free strategy. In this approach, the Friedel–
Crafts alkylation/lactonisation cascade reaction introduced
the α,α‑disubstituted amino benzofuran‑2‑one skeleton.
The antibacterial activity and PDF inhibition assay of
(±)-methoxyfumimycin ethyl ester are currently underway in
our laboratory.
Experimental
Reagents and all solvents were analytically pure grade and were
used without further purification. Column chromatography (CC)
was performed on silica gel (200–300 mesh). Analytical TLC was
performed on pre-coated silica gel GF254 plates (Qingdao Haiyang
Chemical Co. Ltd, Qingdao, P.R. China). Visualisation on TLC was
1
achieved by the use of UV light (254 nm) and treatment with I2; H
(600 or 400 MHz) and 13C (150 MHz) NMR spectra were recorded on a
Bruker Avance 600 MHz spectrometer with CDCl3 as solvent and TMS
as internal standard. Chemical shifts are reported in ppm relative to the
internal reference. ESIMS were obtained on a Waters ZQ4000/2695
HPLC-MS. HRMS were measured on a Finnigan MAT95 mass
spectrometer.
(E)-Methyl-4-(4-allyl-5-hydroxy-6-methoxy-3-methyl-2-oxo-2,3-
dihydrobenzofuran-3-ylamino)-4-oxobut-2-en-oate (8): A solution
of 7 (61 mg, 0.17 mmol) in DMF (3 mL) was heated at 170 °C to reflux
for 16 h. The solvent was removed under reduced pressure; and 10 mL
water was added to the residue. The mixture was extracted with EtOAc
(3×10 mL). The organic phase was washed with saturated brine,
dried over Na2SO4 and concentrated under reduced pressure. Flash
chromatography (PE:acetone=4:1→3:1) afforded 8 as a white solid
(48.8 mg, 80%). 1H NMR δ (CDCl3, ppm, 600 MHz): 1.74 (s, 3H), 3.38
(dd, J=15.6, 6.0 Hz, 1H), 3.47 (dd, J=15.6, 5.4 Hz, 1H), 3.78 (s, 3H),
3.90 (s, 3H), 4.87 (dd, J=16.8, 1.2 Hz, 1H), 4.96 (dd, J=10.2, 1.2 Hz,
1H), 5.51 (brs, 1H, OH), 5.88–5.94 (m, 1H), 6.69 (s, 1H), 6.73 (d,
J=15.6 Hz, 1H), 6.88 (d, J=15.6 Hz, 1H), 7.16 (brs, 1H, NH).
4-Allyloxy-3-methoxybenzaldehyde (3):8 A suspension of vanillin
3 (2.87 g, 18.86 mmol) and K2CO3 (3.64 g, 26.40 mmol) in acetone
(28 mL), was treated with allylbromide (2.10 mL, 24.51 mmol). The
mixture was heated to reflux for 6 h. After filtration, the filtrate was
concentrated under reduced pressure. The crude product was purified
by chromatography on silica gel (PE: AcOEt=10: 1) to afford the
allylether 3 as brown oil (3.55 g, 98%).
4-Allyloxy-3-methoxyphenol (4):8 Boric acid (5.72 g, 92.30 mmol)
was suspended in a mixture of THF (50 mL), H2O2 (30% in H2O,
6 mL) and H2SO4 (2.66 mL, 98%). After stirring for 30 min, 3
(3.55 g,18.47 mmol) was added as solution in THF (20 mL) over
15 min. After additional stirring for 5 h, the mixture was filtered. The
filtrate was neutralised by the addition of sat. NaHCO3 solution; the
aqueous layer was extracted with EtOAc (3×90 mL). The combined
organic extracts were washed with brine (50 mL), dried over Na2SO4
and concentrated under reduced pressure. Flash chromatography (PE:
AcOEt=4:1) afforded the phenol 4 as brown oil (3.06 g, 92%). 1H NMR
δ (CDCl3, ppm, 600 MHz): 3.68 (s, 3H), 4.49 (d, J=6 Hz, 2H), 5.21 (dd,
J=10.2, 1.2 Hz, 1H), 5.32 (dd, J=17.4, 1.2 Hz, 1H), 5.99–6.05 (m, 1H),
6.34 (dd, J=8.4, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.72 (d, J=8.4 Hz,
1H), 7.20 (brs, 1H).
(E)-Ethyl-4-(5-hydroxy-6-methoxy-3-methyl-2-oxo-4-((E)-prop-
1-enyl)-2,3-dihydrobenzofuran-3-ylamino)-4-oxobut-2-enoate
((±)methoxyfumimycin ethyl ester (9): A mixture of 8 (38 mg,
0.11 mmol) and RhCl3·3H2O (5 mg, 19 µmol) in EtOH (2 mL) was
heated to reflux. After 8 h, the reaction was allowed to cool to room
temperature and filtered through a 3 cm pad of Celite. The filtrate
was concentrated under reduced pressure. Flash chromatography
(PE:acetone=5: 1→3:1) afforded 9 as a white solid (E:Z 10:1,
1
26 mg, 68%). H NMR δ (CDCl3, ppm, 600 MHz): 1.30 (t, J=7.2 Hz,
3H), 1.75 (s, 3H), 1.92 (dd, J=6.6, 1.8 Hz, 3H), 3.91 (s, 3H), 4.24
(q, J=7.2 Hz, 2H), 5.82 (s, 1H, OH), 6.31 (dd, J=16.2, 1.8 Hz, 1H),
6.65 (s, 1H), 6.68 (dd, J=16.2, 6.6 Hz, 1H), 6.74 (d, J=15.6 Hz,
H), 6.86 (brs, 1H, NH), 6.92 (d, J=15.6 Hz, 1H). 13C NMR
(CDCl3, ppm): 175.8, 165.3, 162.7, 147.4, 146.3, 140.8, 134.5, 133.8,
132.4, 121.2, 120.5, 116.4, 93.9, 61.4, 58.4, 56.5, 23.5, 19.8, 14.1. (−)
ESI-MS (MeOH): m/z 374.1 [M−H]−, 749.3 [2M−H]−. HRMS (ESI):
m/z [M–H]− calcd for C19H20NO7: 374.1245; found: 374.1248.
L-serine methyl ester hydrochloride (5):14 At 0 °C, thinly chloride
(20 mL, 253.30 mmol) was added dropwise to anhydrous methanol
(100 mL). The solution was stirred at 0 °C for 30 min and then L-serine
(24.50 g, 233.13 mmol) was added. The reaction mixture was stirred
at room temperature for 24 h and TLC (CHCl3/CH3OH, 9:1) indicated
complete disappearance of L-Serine. The reaction mixture was
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