5726
Y. Uto et al. / Bioorg. Med. Chem. 14 (2006) 5721–5728
5.4. General procedure for acetylation: synthesis of 2, 5, 8,
11, and 14
5.5.2. Methyl (E)-3-4-(acetyloxy)-3,5-di[(2E)-3,7-dimeth-
yl-2,6-octadienyl]phenyl-2-propenoate (6). Yield 65%. H
1
NMR (CDCl3) d 7.62 (d, 1H, J = 16.0 Hz), 7.24 (s, 2H),
6.34 (d, 1H, J = 16.0 Hz), 5.23 (t, 2H, J = 7.1 Hz), 5.10
(m, 2H), 3.79 (s, 3H), 3.21 (d, 4H, J = 7.1 Hz), 2.32 (s,
3H), 2.08 (m, 8H), 1.68 (s, 12H), 1.60 (s, 6H); EIMS
m/e: 450 ([MꢀAc]+).
Prenylated p-iodophenol (1, 4, 7, 10, 13) and DMAP
(1.2 mol equiv) were dissolved in dry CH2Cl2, and then
AcCl (2.0 mol equiv) was added dropwise. The mixture
was refluxed for 4 h, the mixture was cooled to room
temperature and evaporated. The residue was chromato-
graphed over silica gel eluated by hexanes/Et2O (10:1) to
afford acetylated compound as colorless oil.
5.5.3. Methyl (E)-3-4-(acetyloxy)-3-[(2E)-3,7-dimethyl-
2,6-octadienyl]phenyl-2-propenoate (9). Yield 91%. 1H
NMR (CDCl3) d 7.65 (d, 1H, J = 16.1 Hz), 7.39 (m,
2H), 7.05 (dd, 1H, J = 7.6 Hz, 1.0 Hz), 6.37 (d, 1H,
J = 16.1 Hz), 5.23 (td, 1H, J = 7.3 Hz, 1.2 Hz), 5.10
(td, 1H, J = 6.6 Hz, 1.2 Hz), 3.80 (s, 3H), 3.25 (d, 2H,
J = 7.3 Hz), 2.32 (s, 3H), 2.08 (m, 4H), 1.70 (s, 3H),
1.68 (s, 3H), 1.60 (s, 3H); EIMS m/e: 356 (M+).
5.4.1. 4-Iodo-2-(3-methyl-2-butenyl)phenyl acetate (2).
1
Yield 96%. H NMR (CDCl3) d 7.52 (m, 2H), 6.77 (d,
1H, J = 8.0 Hz), 5.17 (t, 1H, J = 6.8 Hz), 3.17 (d, 2H,
J = 6.8 Hz), 2.29 (s, 3H), 1.76 (s, 6H).
5.4.2.
2,6-Di[(2E)-3,7-dimethyl-2,6-octadienyl]-4-iod-
ophenyl acetate (5). Yield 88%. 1H NMR (CDCl3) d
7.37 (s, 2H), 5.19 (t, 2H, J = 7.1 Hz), 5.09 (m, 2H),
3.14 (d, 4H, J = 7.1 Hz), 2.29 (s, 3H), 2.06 (m, 8H),
1.69 (s, 6H), 1.66 (s, 6H), 1.60 (s, 6H); EIMS m/e: 491
([MꢀAc]+).
5.5.4. Methyl (E)-3-{4-(acetyloxy)-3-[(2E)-3,7-dimethyl-
2,6-octadienyl]-5-(3-methyl-2-butenyl)phenyl}-2-propeno-
1
ate (12). Yield 91%. H NMR (CDCl3) d 7.62 (d, 1H,
J = 16.0 Hz), 7.23 (s, 2H), 6.35 (d, 1H, J = 16.0 Hz),
5.23 (m, 2H), 5.11 (t, 1H, J = 6.8 Hz), 3.80 (s, 3H),
3.20 (t, 4H, J = 6.3 Hz), 2.32 (s, 3H), 2.09 (m, 4H),
1.76 (s, 3H), 1.69 (s, 6H), 1.68 (s, 3H), 1.61 (s, 3H);
EIMS m/e: 424 (M+).
5.4.3. 2-[(2E)-3,7-Dimethyl-2,6-octadienyl]-4-iodophenyl
acetate (8). Yield 89%. H NMR (CDCl3) d 7.50 (m,
1
2H), 6.77 (d, 1H, J = 8.3 Hz), 5.19 (td, 1H, J = 7.3 Hz,
1.1 Hz), 5.10 (t, 1H, J = 6.7 Hz), 3.19 (d, 2H,
J = 7.3 Hz), 2.30 (s, 3H), 2.07 (m, 4H), 1.69 (s, 3H),
1.67 (s, 3H), 1.61 (s, 3H); EIMS m/e: 398 (M+).
5.5.5. Methyl (E)-3-4-(acetyloxy)-3-[(2E,6E)-3,7,11-tri-
methyl-2,6,10-dodecatrienyl]phenyl-2-propenoate
(15).
7.65 (d, 1H,
Yield 77%. 1H NMR (CDCl3)
d
J = 16.1 Hz), 7.39 (m, 2H), 7.05 (dd, 1H, J = 7.3 Hz,
1.7 Hz), 6.37 (d, 1H, J = 16.1 Hz), 5.23 (td, 1H,
J = 7.3 Hz, 1.2 Hz), 5.10 (m, 2H), 3.80 (s, 3H), 3.26 (d,
2H, J = 7.3 Hz), 2.31 (s, 3H), 2.03 (m, 8H), 1.70 (s,
3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H); EIMS m/
e: 424 (M+).
5.4.4. 2-[(2E)-3,7-Dimethyl-2,6-octadienyl]-4-iodo-6-(3-
methyl-2-butenyl)phenyl acetate (11). Yield 99%. 1H
NMR (CDCl3) d 7.37 (s, 2H), 5.17 (m, 2H), 5.10 (m,
1H), 3.13 (t, 4H, J = 6.3 Hz), 2.30 (s, 3H), 2.08 (m,
4H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.66 (s,
3H), 1.61 (s, 3H); EIMS m/e: 466 (M+).
5.6. General procedure for deprotection: synthesis of
TX-1959, TX-2007, TX-2012, TX-2013, and TX-2101
5.4.5. 4-Iodo-2-[(2E,6E)-3,7,11-trimethyl-2,6,10-dodecat-
rienyl]phenyl acetate (14). Yield 98%. 1H NMR (CDCl3)
d 7.52 (m, 2H), 6.77 (d, 1H, J = 8.3 Hz), 5.19 (td, 1H,
J = 7.3 Hz, 1.2 Hz), 5.10 (m, 2H), 3.19 (d, 2H,
J = 7.3 Hz), 2.29 (s, 3H), 2.05 (m, 8H), 1.76 (s, 3H),
1.67 (s, 3H), 1.60 (s, 6H); EIMS m/e: 466 (M+).
KOH (5% aqueous solution) was added to a solution of
the a, b-unsaturated carboxylate (3, 6, 9, 12, and 15) in
MeOH. The mixture was refluxed for 3 h, cooled to
0 °C, and acidified with 1 N HCl. The MeOH was evap-
orated under reduced pressure, and the aqueous residue
was extracted with Et2O. Extracts were washed with sat-
urated aqueous NaHCO3 and followed saturated aque-
ous NaCl. The Et2O layer was dried (anhydrous
MgSO4) and evaporated under reduced pressure. Resi-
dues were purified by column chromatography on silica
gel (CH2Cl2/MeOH) to give artepillin C isoprene
analogues.
5.5. General procedure for Mizoroki–Heck coupling:
synthesis of 3, 6, 9, 12, 15
A solution of acetylated compound (2, 5, 8, 11, and 14),
methyl acrylate (5.0 mol equiv), Et3N (2.0 mol equiv),
(o-tol)3P (10% mol equiv), and Pd(OAc)2 (5% mol e-
quiv) in dry toluene was refluxed for 20 h. The mixture
was cooled to room temperature, diluted with Et2O,
and filtered through celite. The filtrate was evaporated
under reduced pressure. Residues were purified by col-
umn chromatography on silica gel (hexanes/Et2O) to
give a,b-unsaturated carboxylate as a light yellow oil.
5.6.1. TX-1959 (drupanin19). (E)-3-[4-Hydroxy-3-(3-
methyl-2-butenyl)phenyl]-2-propenoic acid. White solid.
Yield 74%. 1H NMR (CDCl3)
d 7.71 (d, 1H,
J = 15.6 Hz), 7.34 (m, 2H), 6.82 (d, 1H, J = 8.4 Hz),
6.30 (d, 1H, J = 15.6 Hz), 5.31 (t, 1H, J = 6.8 Hz), 3.37
(d, 2H, J = 6.8 Hz), 1.79 (s, 6H). Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.14; H, 6.86.
5.5.1. Methyl (E)-3-[4-(acetyloxy)-3-(3-methyl-2-bute-
nyl)phenyl]-2-propenoate (3). Yield 93%. 1H NMR
(CDCl3) d 7.65 (d, 1H, J = 15.6 Hz), 7.28 (m, 2H),
7.05 (d, 1H, J = 8.8 Hz), 6.38 (d, 1H, J = 15.6 Hz),
5.21 (t, 1H, J = 6.8 Hz), 3.80 (s, 3H), 3.24 (d, 2H,
J = 6.8 Hz), 2.32 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H).
5.6.2. TX-2007. (E)-3-{3,5-Di[(2E)-3,7-dimethyl-2,6-
octadienyl]-4-hydroxyphenyl}-2-propenoic acid. Light
yellow oil. Yield 85%. 1H NMR (CDCl3) d 7.70 (d,