R. J. Payne et al.
MED
3.37 (1H, m, C=CHCH(CH3)2), 1.03 (6H, d, J=6.6 Hz, CH(CH3)2);
13C NMR (100 MHz, CDCl3): d=170.6 (C=O), 163.3 (C=O), 152.4 (C),
145.7 (C), 139.8 (C), 137.5 (CH), 123.8 (Ar CH), 122.0 (Ar CH), 118.5
(Ar CH), 113.6 (C), 52.5 (CH3), 52.0 (CH3), 26.4 (CH), 22.9 (2ꢂCH3); IR
(ATR): nmax =3134 (br), 2959, 2932, 2871, 1729, 1675, 1618, 1588,
1461, 1438 cmꢀ1; HRMS calcd for C15H19O6: [M+H]+, 295.1182,
found: [M+H]+, 295.1173.
was then filtered and rinsed with distilled H2O (4ꢂ3 mL) before the
filtrate was lyophilized to afford the desired inhibitor 40 as a mix-
ture of diastereomers as a rose-colored solid (25 mg, quant, 10:3 Z/
E); mp: 219–2218C; (Z)-41: 1H NMR (400 MHz, D2O): d=7.46 (1H,
dd, J=1.4, 8.0 Hz, Ar H, H-6), 6.91 (1H, dd, J=1.4, 8.0 Hz, Ar H, H-
4), 6.82 (1H, app t, J=8.0 Hz, Ar H, H-5), 6.50 (1H, t, J=7.6 Hz, C=
CHEt), 2.12 (2H, m, J=7.6 Hz, CH2CH3), 0.97 (3H, t, J=7.6 Hz,
CH2CH3); 13C NMR (100 MHz, D2O): d=175.3 (C=O), 169.8 (C=O),
149.4 (C), 145.8 (C), 143.3 (C), 131.6 (CH), 123.0 (Ar CH), 118.8 (C),
3-(1-Carboxy-3-methylbut-1-enyloxy)-2-hydroxybenzoic acid 40.
Diester 35 (51 mg, 0.17 mmol) was reacted for 48 h using Proce-
dure A. The solvent was removed in vacuo prior to acidification to
pH 5–6 with pre-washed Amberlite IR-120 (H+) ion-exchange resin.
The acidified solution was then filtered and rinsed with distilled
H2O (4ꢂ3 mL) before the filtrate was lyophilized to afford the de-
sired inhibitor 40 as a mixture of diastereomers as a pale-orange
1
118.3 (Ar CH), 116.9 (Ar CH), 18.9 (CH2), 12.3 (CH3); (E)-41: H NMR
(400 MHz, D2O): d=7.53 (1H, dd, J=1.4, 8.0 Hz, Ar H, H-6), 7.08
(1H, dd, J=1.4, 8.0 Hz, Ar H, H-4), 6.86 (1H, app t, J=8.0 Hz, Ar H,
H-5), 5.54 (1H, t, J=7.7 Hz, C=CHEt), 2.43 (2H, m, J=7.6, 7.7 Hz,
CH2CH3), 1.00 (3H, t, J=7.6 Hz, CH2CH3); 13C NMR (100 MHz, D2O):
d=175.2 (C=O), 170.1 (C=O), 145.2 (C), 144.8 (C), 124.8 (CH), 124.3
(Ar CH), 120.9 (C), 120.7 (Ar CH), 118.4 (Ar CH), 19.9 (CH2), 13.6
(CH3), one undetected double-up; IR (ATR): nmax =3396 (br), 2968,
1632, 1582, 1463, 1393 cmꢀ1; LRMS [MꢀH]ꢀ 251.20; HRMS calcd for
C12H11O6: [MꢀH]ꢀ, 251.0556, found: [MꢀH]ꢀ, 251.0555.
1
solid (46 mg, quant, 4:1 Z/E); mp: (dec.) 211–2128C; (Z)-40: H NMR
(400 MHz, D2O): d=7.46 (1H, dd, J=1.1, 7.9 Hz, Ar H, H-6), 6.92
(1H, dd, J=1.1, 7.9 Hz, Ar H, H-4), 6.83 (1H, app t, J=7.9 Hz, Ar H,
H-5), 6.31 (1H, d, J=10.0 Hz, C=CHCH(CH3)2), 2.69–2.59 (1H, m, C=
CHCH(CH3)2), 0.98 (6H, d, J=6.4 Hz, CH(CH3)2); 13C NMR (100 MHz,
D2O): d=175.4 (C=O), 170.1 (C=O), 149.4 (C), 146.0 (C), 142.2 (C),
136.2 (CH), 122.9 (Ar CH), 118.9 (C), 118.3 (Ar CH), 116.9 (Ar CH),
25.4 (CH2), 21.3 (2ꢂCH3); (E)-40: 1H NMR (400 MHz, D2O): d=7.53
(1H, dd, J=0.8, 7.7 Hz, Ar H, H-6), 7.09 (1H, dd, J=2.0, 7.7 Hz, Ar
H, H-4), 6.87 (1H, app t, J=7.7 Hz, Ar H, H-5), 5.33 (1H, d, J=
10.4 Hz, C=CHCH(CH3)2), 3.24–3.16 (1H, m, C=CHCH(CH3)2), 1.00
(6H, d, J=6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, D2O): d=175.3 (C=
O), 170.2 (C=O), 150.6 (C), 144.8 (C), 144.5 (C), 129.4 (CH), 124.3 (Ar
CH), 120.7 (Ar CH), 119.2 (C), 118.4 (Ar CH), 116.0 (Ar CH), 26.0 (CH),
22.5 (2ꢂCH3); IR (ATR): nmax =3216 (br), 2922, 2850, 1700, 1657,
1590, 1384 cmꢀ1; LRMS [MꢀH]ꢀ 265.20; HRMS calcd for C13H14O6Na:
[M+Na]+, 289.0688, found: [M+Na]+, 289.0683.
Methyl
2-hydroxy-3-(3-methoxy-3-oxo-1-phenylprop-1-en-2-
yloxy)benzoate 37. Phosphonate 32 (150 mg, 0.43 mmol) and
benzaldehyde (0.09 mL, 0.86 mmol) were reacted for 5 h at ꢀ788C
and 11 h at room temperature under Procedure D. The product
was purified by column chromatography (eluent: hexane/EtOAc
5:1 v/v) to afford diester 37 as a mixture of diastereomers as a col-
orless oil (120 mg, 85%, 1:1 Z/E). Rf [hexane/EtOAc 5:1 v/v]=0.33;
major diastereomer: 1H NMR (400 MHz, CDCl3): d=11.08 (1H, s,
OH), 7.75–7.73 (1H, m, Ar H, C=CHPh), 7.53 (1H, dd, J=1.2, 8.0 Hz,
Ar H, H-6), 7.39 (1H, s, C=CHPh), 7.36–7.32 (4H, m, Ar H, C=CHPh),
6.98 (1H, dd, J=1.2, 8.0 Hz, Ar H, H-4), 6.72 (1H, app t, J=8.0 Hz,
Ar H, H-5), 3.96 (6H, s, 2ꢂCO2Me); 13C NMR (100 MHz, CDCl3): d=
170.7 (C=O), 163.9 (C=O), 152.0 (C), 145.0 (C), 140.0 (C), 132.4 (C),
130.5 (2ꢂAr CH), 129.8 (Ar CH), 128.8 (2ꢂAr CH), 127.4 (CH), 123.6
(Ar CH), 120.0 (Ar CH), 118.5 (Ar CH), 113.7 (C), 52.6 (2ꢂCH3); minor
diastereomer: 1H NMR (400 MHz, CDCl3): d=11.03 (1H, s, OH),
7.75–7.73 (1H, m, Ar H, C=CHPh), 7.64 (1H, dd, J=1.2, 7.9 Hz, Ar H,
H-6), 7.36–7.32 (4H, m, Ar H, C=CHPh), 7.25 (1H, dd, J=1.2, 7.9 Hz,
Ar H, H-4), 6.85 (1H, app t, J=7.9 Hz, Ar H, H-5), 6.57 (1H, s, C=
CHPh), 3.76 (3H, s, CO2Me), 3.70 (3H, s, CO2Me); 13C NMR (100 MHz,
CDCl3): d=170.5 (C=O), 163.4 (C=O), 153.0 (C), 144.3 (C), 143.3 (C),
133.2 (C), 129.0 (2ꢂAr CH), 128.1 (2ꢂAr CH), 128.1 (Ar CH), 125.2
(Ar CH), 124.6 (Ar CH), 122.5 (CH), 118.8 (Ar CH), 114.0 (C), 52.6
(CH3), 52.3 (CH3); IR (ATR): nmax =3101 (br), 2955, 1729, 1679, 1463,
1440, 1251 cmꢀ1; HRMS calcd for C18H17O6: [M+H]+, 329.1025,
found: [M+H]+, 329.1018.
Methyl
2-hydroxy-3-(1-methoxy-1-oxopent-2-en-2-yloxy)ben-
zoate 36. Phosphonate 32 (150 mg, 0.43 mmol) and propionalde-
hyde (0.06 mL, 0.86 mmol) were reacted for 1 h at ꢀ788C under
Procedure D. The product was purified by column chromatography
(eluent: hexane/EtOAc 5:1 v/v) to afford diester 36 as a mixture of
diastereomers as a light-yellow solid (92 mg, 77%, 3:2 Z/E); mp:
73–758C; (Z)-36: Rf [hexane/EtOAc 5:1 v/v]=0.60; 1H NMR
(400 MHz, CDCl3): d=11.08 (1H, s, OH), 7.50 (1H, dd, J=1.3, 8.0 Hz,
Ar H, H-6), 6.89 (1H, dd, J=1.3 Hz, Ar H, H-4), 6.74 (1H, app t, J=
8.0 Hz, Ar H, H-5), 6.66 (1H, t, J=7.7 Hz, C=CHEt), 3.95 (3H, s,
CO2Me), 3.69 (3H, s, CO2Me), 2.31–2.20 (2H, m, CH2CH3), 1.03 (3H,
t, J=7.6 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3): d=170.7 (C=O),
163.4 (C=O), 151.8 (C), 146.2 (C), 140.6 (C), 134.0 (CH), 123.0 (Ar
CH), 119.3 (Ar CH), 118.4 (Ar CH), 113.6 (C), 52.6 (CH3), 52.3 (CH3),
19.4 (CH2), 13.0 (CH3). (E)-36: Rf [hexane/EtOAc 5:1 v/v]=0.64;
1H NMR (400 MHz, CDCl3): d=11.01 (1H, s, OH), 7.55 (1H, dd, J=
1.4, 8.0 Hz, Ar H, H-6), 7.03 (1H, dd, J=1.4, 8.0 Hz, Ar H, H-4), 6.79
(1H, app t, J=8.0 Hz, Ar H, H-5), 5.81 (1H, t, J=7.9 Hz, C=CHEt),
3.95 (3H, s, CO2Me), 3.74 (3H, s, CO2Me), 2.65–2.54 (2H, m,
CH2CH3), 1.04 (3H, t, J=7.5 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3):
d=170.7 (C=O), 164.0 (C=O), 152.6 (C), 145.6 (C), 141.2 (C), 131.8
(CH), 124.1 (Ar CH), 122.6 (Ar CH), 118.6 (Ar CH), 113.7 (C), 52.6
(CH3), 52.1 (CH3), 20.5 (CH2), 14.0 (CH3); IR (ATR): nmax =3131 (br),
2956, 1728, 1674, 1456 1437, 1243, 1226 cmꢀ1; LRMS [M+H]+
280.87; HRMS calcd for C14H16O6Na: [M+Na]+, 303.0845, found:
[M+Na]+, 303.0839.
3-(1-carboxy-2-phenylvinyloxy)-2-hydroxybenzoic acid 42. Die-
ster 37 (75 mg, 0.23 mmol) was reacted for 48 h using Procedure A.
The solvent was removed in vacuo prior to acidification to pH 5–6
with pre-washed Amberlite IR-120 (H+) ion-exchange resin. The
acidified solution was then filtered and rinsed with distilled H2O
(4ꢂ3 mL) before the filtrate was lyophilized to afford the inhibitor
42 as a mixture of diastereomers as a pale-pink solid (67 mg, 98%,
1:1 Z/E); mp: (dec.) 235–2378C; one diastereomer: 1H NMR
(400 MHz, D2O): d=7.70–7.67 (1H, m, Ar H, C=CHPh), 7.46 (1H, dd,
J=1.5, 8.0 Hz, Ar H, H-6), 7.39–7.27 (4H, m, Ar H, C=CHPh), 7.25
(1H, s, C=CHPh), 6.94 (1H, dd, J=1.5, 8.0 Hz, Ar H, H-4), 6.77 (1H,
app t, J=8.0 Hz, Ar H, H-5); 13C NMR (100 MHz, D2O): d=175.3 (C=
O), 170.9 (C=O), 150.2 (C), 149.7 (C), 142.8 (C), 133.0 (C), 129.6 (2ꢂ
Ar CH), 129.1 (Ar CH), 128.4 (2ꢂAr CH), 127.1 (Ar CH), 124.1 (CH),
3-(1-Carboxybut-1-enyloxy)-2-hydroxybenzoic acid 41. Selected
chromatographic fractions of diester 36 (28 mg, 0.10 mmol, 10:3 Z/
E) were reacted for 48 h using Procedure A. The solvent was re-
moved in vacuo prior to acidification to pH 5–6 with pre-washed
Amberlite IR-120 (H+) ion-exchange resin. The acidified solution
1
119.1 (C), 118.3 (Ar CH), 117.1 (Ar CH); other diastereomer: H NMR
(400 MHz, D2O): d=7.70–7.67 (1H, m, Ar H, C=CHPh), 7.62 (1H, dd,
J=1.6, 8.0 Hz, Ar H, H-6), 7.39–7.27 (4H, m, Ar H, C=CHPh), 7.25
1078
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 1067 – 1079