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doi.org/10.1002/cctc.202001296
ChemCatChem
then the solution was dried by adding Na2SO4. After removal of the
precipitate and Na2SO4 by filtration under reduced pressure over a
celite pad, the solution was evaporated under reduced pressure to
obtain a crude mixture. The material was purified over silica gel
(20:1, w/w) by elution with cyclohexane/ethyl acetate (7:3, v/v) to
give pure 3f (299 mg, 1.65 mmol, yield 43%). 1H NMR (300 MHz,
CDCl3) δ 6.69–6.56 (m, 3H), 3.79 (t, 2H), 2.75 (t, 2H), 1.64 (s, 6H). 13C
NMR (75 MHz, CDCl3) δ 147.83, 146.25, 131.55, 121.42, 117.90,
109.25, 108.29, 63.95, 39.07, 26.02.
of catechol underwent O-methylation in para position, which
opposite to the substrates bearing a polar side chain, which
were methylated preferentially in meta-position.
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Experimental Section
General Information
1H and 13C NMR spectra were recorded at 20 C on a 300MHz Bruker
Hydroxytyrosol 1f. Amberlyst 15 (350 mg) was added to a solution
of 3f (299 mg, 1.65 mmol) in MeOH (23 mL), and the suspension
was refluxed under stirring for 8 h while the reaction progress was
monitored by TLC. Finally, the resin was removed by filtration, and
the resulting solution was evaporated under reduced pressure to
the crude product which was purified via column chromatography
cyclohexane/EtOAc (8:2 v/v) to afford 1f (201 mg, 1.3 mmol, yield
78%). Spectroscopic data were superimposable with those of the
°
NMR. The conversions and regiomeric ratio of all biotransformations
were measured by reversed-phase HPLC with an Agilent 1260
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Infinity HPLC system at 25 C, using a Phenomenex Luna® 5 mm,
C18, 100 A (250×4.6 mm) column. Detection was performed with a
diode array detector (G4212B). TLC was carried out with pre-coated
aluminum sheets (TLC Silica gel 60 F254, Merck) with detection by
UV (254 nm) and/or by staining with cerium molybdate solution. All
chemicals and solvents were obtained from commercial suppliers
(TCI, Sigma Aldrich/Fluka, VWR International/Merck, Roth) and used
as received unless stated otherwise. Commercial available com-
pounds were utilized as obtained as references for the quantitative
and qualitative determination of the isomers produced during the
biotransformation. In the case that the references were not
commercially available, they were synthesized. 3-Hydroxytyrosol
(1f) was synthesized following a procedure from literature.[25] Units
are defined as converted substrate in μmol per min.
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pure standard of 1f. H NMR (300 MHz, MeOD) δ 6.66 (m, J=7.3,
5.0 Hz, 1H), 6.52 (m, J=8.0, 2.1 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 2.66
(t, J=7.2 Hz, 2H). 13C NMR (75 MHz, MeOD) δ 146.14, 144.62, 131.77,
121.19, 117.05, 116.29, 64.60, 39.67.
5-(2-hydroxyethyl)-2-methoxyphenol p-2f. A solution of commer-
cially available 2-(3-hydroxy-4-methoxyphenyl)acetic acid (315 mg,
1.5 mmol) in anhydrous THF (5 mL) was added dropwise over
15 min to a solution of dry THF (5 mL) and LiAlH4 (236 mg, 6 mmol)
°
under Ar atm and 0 C. The suspension was left stirring for 4 h at
°
0 C. The mixture was then cooled, and excess hydride was
cautiously decomposed by adding NaOH (0.75 M, 1 mL), until the
formation of a white precipitate occurred; then the solution was
dried (Na2SO4). After removal of the precipitate and Na2SO4 by
filtration under reduced pressure over a celite pad, and washed
with MeOH the solution was evaporated under reduced pressure to
obtain a crude mixture. The material was purified over silica gel
(20:1, w/w) by elution with cyclohexane/EtOAc (7:3 v/v) to give
pure p-2f (103 mg, 0.61 mmol, yield 41%). 1H NMR (300 MHz,
MeOD) δ 6.90–6.81 (m, 1H), 6.76–6.63 (m, 2H), 3.84 (s, 3H), 3.73 (t,
J=7.2 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H). 13C NMR (75 MHz, MeOD) δ
147.50, 147.40, 133.19, 121.09, 116.99, 112.84, 64.46, 56.47, 39.63.
Synthetic Procedures
3,4-Dihydroxyphenyl)acetic methyl ester 5f. Concentrated H2SO4
(5 drops) was added to a solution of 3,4-dihydroxyphenylacetic acid
(1 g, 5.95 mmol) in MeOH (95 mL) under argon atmosphere in the
dark and the reaction was refluxed for 2 h. After solvent evapo-
ration under reduced pressure, the residue was redissolved in
EtOAc and washed with sat. aqu. NaHCO3 (20 ml). The aqueous
phase was extracted with EtOAc (3×30 mL), and the combined
organic extracts were washed with brine (30 ml), dried over Na2SO4,
and evaporated under reduced pressure to give the pure ester 5f
(900 mg, 5.3 mmol, yield 84%). 1H NMR (300, MeOD) δ 6.70–6.68
(m, 2H), 6.58–6.52 (m, 1H), 3.66 (s, 3H), 3.46 (s, 2H). 13C NMR
(75 MHz, MeOD) δ 174.53, 146.27, 145.42, 126.89, 121.60, 117.30,
116.26, 52.36, 41.15.
5-(1-hydroxyethyl)-2-methoxyphenol p-3 h. Isovanillin (6.6 mmol,
1 g, 1 eq) previously dissolved in anh. THF (4 ml) was added
dropwise over 15 minutes to a stirred solution of MeMgI (3 M in
°
Et2O, 13.2 mmol, 4.4 mL, 2 eq) under Ar atm at 0 C. The mixture
°
°
was left stirring for 3 hours at 35 C. It was then cooled to 0 C again
and aqueous HCl (1 M, 6.6 mL) was carefully added. The resulting
aqueous phase was extracted with EtOAc (3×35 mL). The com-
bined organic fractions were dried using Na2SO4. After removal of
Na2SO4 by filtration, the solution was evaporated under reduced
pressure. After purification via column chromatography (c-hex:
EtOAc, 7:3 v/v) p-3 h was obtained as a yellow oil (2.7 mmol,
2-(2,2-Dimethylbenzo[1,3]dioxol-5-yl)acetic methyl ester 4f.
Under argon atmosphere in the dark, 2,2-dimethoxypropane
(6.5 mL, 53 mmol, 9 eq) and p-toluene sulfonic acid (186 mg,
0.98 mmol, 0.16 eq) were added to a solution of 5f (900 mg,
5.3 mmol, 1 eq) in anhydrous CH2Cl2 (180 mL), and the solution was
refluxed for 8 h. The reaction mixture was neutralized by shaking
with sat. aqu. NaHCO3 (30 ml), and the resulting aqueous phase was
extracted three times with CHCl3 (3×20 mL). The combined organic
extracts were dried (Na2SO4) and evaporated under reduced
pressure. The crude residue was purified via column chromatog-
raphy using silica gel (20:1, w/w) by elution with cyclohexane/
EtOAc (8:2 v/v) to furnish pure 4f (849 mg, 3.82 mmol, yield 72%).
1H NMR (300 MHz, MeOD) δ 6.65 (d, J=5.3 Hz, 3H), 3.66 (s, 3H), 3.52
(s, 2H), 1.63 (s, 6H). 13C NMR (75 MHz, MeOD) δ 174.17, 148.91,
147.89, 128.51, 122.90, 119.02, 110.40, 108.86, 52.42, 41.32, 25.91.
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410 mg, 31% yield). H NMR (300 MHz, MeOD) δ 6.85 (dd, J=5.3,
2.9 Hz, 2H), 6.78 (dd, J=8.3, 2.0 Hz, 1H), 4.70 (q, J=6.5 Hz, 1H), 3.82
(s, 3H), 1.39 (d, J=6.5 Hz, 3H). 13C NMR (75 MHz, MeOD) δ 148.10,
147.36, 140.49, 117.81, 113.67, 112.46, 70.53, 56.43, 25.46.
5-ethyl-2-methoxyphenol p-2 h. Pd/C (10% wt, 0.44 mmol,
462 mg, 0.16 eq) was added to a stirred solution of p-3 h (2.7 mmol,
410 mg, 1 eq) in MeOH (90 ml), then HClO4 (70% wt, 895 μl) was
added. The mixture was left stirring for 16 hours at room temper-
ature under H2 atmosphere (1 atm). The crude mixture was filtrated
over celite and then NaHCO3 (sat. aqu. solution, 75 ml) was added.
The resulting aqueous phase was extracted with CH2Cl2 (3×40 ml),
dried over Na2SO4 and evaporated under reduced pressure. The
crude product was then purified via column chromatography (c-
hexane/EtOAc, 7:3 v/v) to obtain the pure p-2h as brown oil
2-(2,2-Dimethylbenzo[1,3]dioxol-5-yl)ethanol 3f. A solution of
ester 4f (849 mg, 3.82 mmol) in anhydrous Et2O (16 mL) was added
dropwise to a solution of dry Et2O (20 mL) and LiAlH4 (77.4 mg,
°
2.05 mmol) under Ar atm at 0 C. The suspension was left stirring
°
for 3 h at 0 C. The mixture was then cooled, and excess hydride
was cautiously decomposed by adding an aqueous NaOH solution
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(1.44 mmol, 219 mg, 59% yield). H NMR (300 MHz, MeOD) δ 6.77
(0.75 M, 350 μL), until the formation of a white precipitate occurred;
ChemCatChem 2020, 12, 1–8
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