Synthesis and biological evaluation of gallic acid analogs

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Maurizio Barontini,a Ilaria Proietti Silvestri,*b Valentina Nardi,b Fernanda Crisante,b Gaetano Pepe,c
Luigi Pari,a Francesco Gallucci,a Paolo Bovicellid and Giuliana Righie
Synthesis and biological evaluation of gallic acid
analogs
a
CRA-ING, Via della Pascolare, 16 - 00016 Monterotondo, Italy
b
Dep. Of Chemistry, “Sapienza” University of Rome, P.le A. Moro, 5 – 00185 Rome, Italy.
c
Department of Agrobiology and Agrochemistry, University of Tuscia, 01100,Viterbo, Italy
d
CNR ICB-Unity of Sassari, Traversa La Crucca 3 – Baldanica I – 07040 Sassari, Italy
CNR ICB - Unity of Rome, c/o Dep. Of Chemistry “Sapienza” University of Rome, P.le A. Moro, 5
– 00185 Rome, Italy
e
Supporting information
Identification and characterization of products
1
H- NMR and 13C NMR were recorded on a Varian Mercury 3000 instrument ( 1H, 300 MHz; 13C, 75 MHz). All
chemical shifts are expressed in parts per million (δ scale) and coupling constants in Hertz (Hz). HRMS were performed
on a Q-TOF MICRO spectrometer (Micromass, now Waters, Manchester, UK) equipped with an ESI source. Melting
points were measured on a Mettler FP80 instrument and were uncorrected. All chromatographic purifications were
performed on silica gel (100-200 mesh from E. Merck, Germany). Thin layer chromatography (TLC) was performed on
precoated silica gel 60 F254 aluminium sheets (Merck, Italy) and spots were visualized under UV torch. Organic solvents
used for the chemical synthesis and for chromatography acquired from Sigma-Aldrich were of analytical grade.
Synthesis of 4-hydroxy-3,5-dimethoxyphenethyl ethanoate (9).
OAc
MeO
OMe
OH
H NMR (CDC13) δ ppm: 2.02 (3H, s), 2.83 (2H, t, J 6.9 Hz), 3.83 (6H, s), 4.22 (2H, t, J 6.9 Hz), 6.40 (2H, s), 13C
NMR (CDC13) δ ppm: 21.0, 35.2, 56.3, 65.1, 105.5, 128.7, 133.4, 147.0, 171.0; HRMS (ESI) m/z calcd for C12H16O5
240.0998 [M]+, found 240.1012. Anal. calcd. for C12H16O5 (240.25): C, 59.99; H, 6.71. Found: C, 60.02; H, 6.74.
1
Synthesis of 4-hydroxyphenethyl methyl carbonate (12).
O
O
OH
O
H NMR (CDC13) δ ppm: 2.88 (2 H, t, J 7.1 Hz), 3.75 (3H, s), 4.28 (2H, t, J 7.1 Hz), 5.37 (1H, s), 6.75 (2H, d, J 8.6
Hz), 7.06 (2H, d, J 8.5 Hz); 13C NMR (CDC13) δ ppm: 34.2, 54.8, 68.7, 115.4, 129.1,130.0, 154.4, 155.8; HRMS (ESI)
m/z calcd for C10H12O4 196.0736 [M]+, found 196.0711. Anal. calcd. for C10H12O4 (196.20): C, 61.22; H, 6.16. Found:
C, 61.15; H, 6.22.
1
Bromination procedure.
2,6-dibromo-4-(2-hydroxy-ethyl)-phenol (6)
OH
Br
Br
OH
H NMR (CDC13) δ ppm: 2.74 (2H, t, J 6.6 Hz), 3.80 (2H, t, J 6.6 Hz), 6.00 (1H, s), 7.31 (2H, s), 13C NMR (CDC13) δ
ppm: 37.7, 63.3, 110.0, 132.6, 133.4, 148.2. HRMS (ESI) m/z calcd for C8H8Br2O2 293.8891 [M]+, found 293.8910.
1
3,5-dibromo-4-hydroxyphenethyl methyl carbonate (13)
O
O
O
Br
Br
OH
H NMR (CDC13) δ ppm: 2.86 (2H, t, J 6.8 Hz), 3.77 (3H, s), 4.28 (2H, t, J 6.8 Hz), 7.31 (2H, s); 13C NMR (CDC13) δ
ppm: 33.3, 54.6, 67.5, 109.7, 131.7, 132.1, 148.1, 155.3; HRMS (ESI) m/z calcd for C10H10Br2O4 351.8946 [M]+, found
351.8975.
1
Methanolysis procedure.
4-hydroxy-3,5-dimethoxyphenethyl methyl carbonate (8)
O
O
MeO
O
OMe
OH
Rf (33% EtOAc/Hexane) 0.45; 1H NMR (CDC13) δ ppm: 2.88 (2H, t, J 7.2 Hz), 3.75 (3H, s), 3.84 (6H, s), 4.29 (2H, t, J
7.2 Hz), 6.43 (2H, s); 13C NMR (CDC13) δ ppm: 35.2, 54.6, 56.2, 68.4, 105.5, 128.1, 133.5, 147.0, 155.6. HRMS (ESI)
m/z calcd for C12H16O6 256.0947 [M]+, found 256.0958. Anal. calcd for C12H16O6 (256.25): C, 56.24; H, 6.29. Found: C,
56.18; H, 6.24.
4-hydroxy-3,5-dimethoxyphenethyl alcohol (7)
OH
MeO
OMe
OH
Rf (33% EtOAc/Hexane) 0.25; 1H NMR (CDC13) δ ppm: 2.76 (2H, t, J 6.6 Hz), 3.80 (2H, t, J 6.6 Hz), 3.83 (6H, s),
6.42 (2H, s); 13C NMR (CDC13) δ ppm: 39.2, 56.2, 63.7, 105.4, 129.3, 133.2, 147.0; HRMS (ESI) m/z calcd for
C10H14O4 198.0892 [M]+, found 198.0906. Anal. calcd for C10H14O4 (198.22): C, 60.59; H, 7.12. Found: C, 60.55; H,
7.08.
Demethylation procedure.
3,4,5-trihydroxyphenethyl methyl carbonate (14)
O
O
HO
O
OH
OH
H NMR (CDCl3) δ ppm: 2.74 (2H, t, J 7.2 Hz), 3.74 (3H, s), 4.23 (2H, t, J 7.2 Hz), 6.31 (2H, s); 13C NMR (CDCl3) δ
ppm: 34.6, 54.9, 68.6, 108.6, 129.5, 130.4, 144.3, 161.0; HRMS (ESI) m/z calcd for C10H12O6 228.0634 [M]+, found
228.0606. Anal. calcd for C10H12O5 (212.20): C, 56.60; H, 5.70. Found: C, 56.55; H, 5.58.
1
3,4,5-trihydroxyphenethyl ethanoate (10)
OAc
HO
OH
OH
H NMR (CDCl3) δ ppm: 1.98 (3H, s), 2.70 (2H, t, J 7.2 Hz), 4.15 (2H, t, J 7.2 Hz), 6.17 (1H, broad s), 6.28 (2H, broad
s),6.76 (2H, s); 13C NMR (CDCl3) δ ppm: 34.4, 65.0, 108.2, 117.6, 130.2, 130.9, 145.5, 171.0; HRMS (ESI) m/z calcd
for C10H12O5 212.0685 [M]+, found 212.0669. Anal. calcd for C10H12O5 (212.20): C, 56.60; H, 5.70. Found: C, 56.55;
H, 5.58.
1
Synthesis of 3,4,5-trihydroxyphenetil alcohol (11).
OH
HO
OH
OH
H NMR (CDC13) δ ppm: 2.45 (2H, t, J 6.6 Hz), 3.54 (2H, t, J 6.6 Hz), 6.20 (2H, s); 13C NMR (CDC13) δ
62.7, 109.0, 131.7, 131.8, 145.4; HRMS (ESI) m/z calcd for C8H10O4 170.0579 [M]+, found 170.0534. Anal. calcd for
C8H10O4 (170.06): C, 56.47; H, 5.92. Found: C, 56.45; H, 5.80.
1
Synthesis of 3,4,5-trihydroxyphenetil alcohol methylether (15).
OMe
HO
OH
OH
H NMR (D2O) δ ppm: 2.59 (2H, t, J 6.6 Hz), 3.54 (3H, s), 3.56 (2H, t, J 6.6 Hz), 6.23 (2H, s); 13C NMR (D2O) δ ppm:
33.8, 58.4, 74.5, 109.1, 128.9, 135.6, 145.8; HRMS (ESI) m/z calcd for C9H12O4 184.0736 [M]+, found 184.0752. Anal.
calcd for C9H12O4 (184.19): C, 58.69; H, 6.57. Found: C, 58.65; H, 6.58.
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